Preventives/remedies for urinary disturbance

ABSTRACT

Preventives/remedies for voiding disturbance containing a compound having both of an acetylcholinesterase inhibitory action and an α1 antagonistic action which exhibits an excellent effect of improving the urinary function of the bladder (i.e., effects of improving urine flow rate and voiding efficiency) without affecting the urinary pressure or the blood pressure.

This is a Rule 1.53(b) divisional of Ser. No. 10/500,217 filed Jun. 25,2004 which is a U.S. National Stage of International Application No.PCT/JP02/13653 filed Dec. 26, 2002.

TECHNICAL FIELD

The present invention relates to medicines, more particularly,preventives/remedies for voiding disturbance.

BACKGROUND ART

Lower urinary tract disease is a generic term for subjective orobjective abnormality during a process from storage of urine (urinarystorage) to excretion of urine (urination), and is classified intourinary storage disturbance (urinary incontinence, voiding frequencyetc.), and voiding disturbance (voiding difficulty, micturition pain,urinary tract obstruction etc.). Although lower urinary tract disease isalso observed in young people, with progression of an aging society,lower urinary tract disease of the elderly, particularly, voidingdisturbance, inter alia, voiding difficulty accompanied with benignprostatic hyperplasia has become a great social problem recently.

Urination is controlled by a peripheral nervous system composed ofparasympathetic nerve such as pelvic nerve, sympathetic nerve such ashypogastric nerve and somatic nerve such as pudic nerve under control ofmicturition center, and it is suggested that various neurotransmitters(e.g. acetylcholine, noradrenaline, ATP, substance P, neuropeptide Yetc.) are involved in micturition.

As a therapeutic agent for voiding disturbance, in particular, voidingdifficulty, a medicine for augmenting a contractile force of bladdermuscle (detrusor muscle), or a medicine for relaxing urethral smoothmuscle and alleviating urethra resistance is used. As a medicine whichacts on bladder muscle and augments its contractile force, a cholineagonist such as bethanechol, and acetylcholinesterase inhibitor such asdistigmine are used. However, for example, bethanechol constricts alsobladder muscle at a urinary storage stage and damages urinary storagefunction of bladder and, at the same time, has side effects such aslacrimation, sweating, gastrointestinal disorder, and bellyache and,therefore, is contraindicated to pregnant woman, digestive ulcer,organic ileus, asthma, and hyperthyroidism. Satisfactory medicines havenot been found out yet.

As an acetylcholinesterase inhibitor having augmenting action of abladder muscle contractile force, for example, distigmine andneostigmine are known. Since an acetylcholinesterase inhibitorpotentiates an action of acetylcholine which is released from a pelvicnerve terminal during voiding, it augments the contraction of a bladdermuscle during voiding, and is an excellent drug in view of physiologicalmechanism of voiding. However, for example, while distigmine contracts abladder muscle, it contracts urethral sphincter muscle due to its strongnicotinic action and increases urethral resistance, resulting in adeteriorated voiding efficiency and insufficient clinical effect.Further, a risk of high pressure voiding is pointed out. In addition,since neostigmine has short-lasting action, it is not used in therapy(see, for example, Non-Patent Document 1).

As a medicine for relaxing urethra smooth muscle and alleviatingurethral resistance, an α₁ receptor antagonist such as tamsulosin,prazosin, alfuzosin, naftopidil and urapidil is used, and it is reportedthat the antagonist has the effect of improving subjective symptom suchas residual urine feeling and nocturia. However, the antagonist has anantihypertensive effect such as orthostatic hypotension as side effect,and an attention must be paid to therapy.

On the other hand, Patent Document 1 discloses an acetylcholinesteraseinhibitor used as a preventive or a therapeutic agent for voidingdisturbance (voiding difficulty), and it is reported that a urine flowrate is considerably improved by using a combination of an α₁ receptorantagonist and an acetylcholinesterase inhibitor. However, concomitantuse of two agents is not satisfactory in terms of therapy andtherapeutic economy considering the burden of a patient to which agentsare administered and the trouble of compounding and the like. Inaddition, a possibility that exacerbation of side effect and deathaccident might occur by drug interaction due to concomitant use ispointed out, and a sufficient attention must be paid thereto.

In addition, amine compound having various pharmacological activitiesare reported as follows:

(1) Patent Document 2 discloses, for example, compounds of the followingformulas, as an acetylcholinesterase inhibitor used as a therapeutic forAlzheimer-type dementia.

(2) Patent Document 3 discloses, for example, a compound of thefollowing formula, as a σ ligand used as a therapeutic for centralnervous disease.

(3) Patent Document 4 discloses, for example, a compound of thefollowing formula, as a synthetic intermediate for a sulfur-containingcompound.

(4) Patent Document 5 discloses, for example, a compound of thefollowing formula, as a derivative of 4-aminobutyrophenones used as atranquilizer.

(5) Patent Document 6 discloses, for example, a compound of thefollowing formula, as a compound used as an antibacterial agent.

(6) Patent Document 7 discloses, for example, a compound of thefollowing formula, as a 5-HT4 receptor ligand.

(7) Non-Patent Document 2 discloses, for example, a compound of thefollowing formula, as a 5-HT4 receptor antagonist.

(8) Patent Document 8 discloses, for example, a compound of thefollowing formula, as a compound having thermogenesis promoting activityand anti-obesity activity.

(9) Patent Document 9 discloses, for example, a compound of thefollowing formula, as an acetylcholinesterase inhibitor.

(10) Patent Document 10 discloses, for example, a compound of thefollowing formula, as an acetylcholinesterase inhibitor used as atherapeutic for Alzheimer-type dementia.

(11) Patent Document 11 discloses, for example, a compound of thefollowing formula, as an acetylcholinesterase inhibitor used as atherapeutic for Alzheimer-type dementia.

(12) Patent Document 12 discloses, for example, a compound of thefollowing formula, as a compound used as a depressor or anantiarrhythmic.

(13) Patent Document 13 discloses, for example, a compound of thefollowing formula, as an acetylcholinesterase inhibitor used as atherapeutic for Alzheimer-type dementia.

(14) Patent Document 14 discloses, for example, a compound of thefollowing formula, as an acetylcholinesterase inhibitor used as atherapeutic for Alzheimer-type dementia.

(15) Patent Document 15 discloses, for example, a compound having thefollowing formula, as an acetylcholinesterase inhibitor used as atherapeutic for Alzheimer-type dementia.

(16) Patent Document 16 discloses, for example, a compound having thefollowing formula, as an acetylcholinesterase inhibitor used as atherapeutic for Alzheimer-type dementia.

However, a compound having both of an acetylcholinesterase inhibitoryactivity and an α₁ receptor antagonistic activity and effect thereof asa preventive or a therapeutic agent for voiding disturbance (voidingdifficulty) have not been reported, suggested or disclosed at all untilnow.

In addition, as a method for assessing a therapeutic agent for voidingdisturbance accompanied with benign prostatic hyperplasia in vivo, forexample, Non-Patent Documents 3 to 5 disclose a method for measuringreduction of intraurethral pressure due to drug administration using ananimal loaded with phenylephrine. However, this method is a procedurefor observing the change of intraurethral pressure, and can not measurea urine flow at that time.

On the other hand, as a method for assessing an intraurethral(intravesical) pressure and an urine flow at the same time, PressureFlow Study is known. For example, there is a description regardingapplication of Pressure Flow Study to a human in Non-Patent Document 6.In addition, Non-Patent Documents 7 to 9 disclose Pressure Flow Study inan experimental animal. However, these Documents do not disclose a caseusing an animal model loaded with phenylephrine, and assessment of atherapeutic agent for voiding disturbance accompanied with benignprostatic hyperplasia can not be properly carried out.

[Non-Patent Document 1]

“Diagnosis and Therapy of Neurogenic Bladder” 2^(nd) edition, TakamichiHattori, Kosaku Yasuda, Igakushoin p. 105–106, p. 139

[Non-Patent Document 2]

Bioorganic and Medicinal Chemistry Letters, 1995, vol. 5, P. 2119–2122

[Non-Patent Document 3]

The Journal of Pharmacology and Experimental Therapeutics, 1999, vol.291, p. 81

[Non-Patent Document 4]

The Journal of Pharmacology and Experimental Therapeutics, 2002. vol.300, p. 487

[Non-Patent Document 5]

The Journal of Pharmacology and Experimental Therapeutics, 2002. vol.300, p. 495

[Non-Patent Document 6]

The mechanics and hydrodynamics of the lower urinary tract, Medicalphysical handbooks. Bristol, 1980

[Non-Patent Document 7]

The Journal of Urology, 1995, vol. 154, p. 580

[Non-Patent Document 8]

American Journal of Physiology, 1995, vol. 269, p. 98

[Non-Patent Document 9]

Neurourology and Urodynamics, 1996, vol. 15, p. 513

[Patent Document 1]

EP-A 1118322

[Patent Document 2]

EP-A 562832

[Patent Document 3]

WO 95/131

[Patent Document 4]

GB 1489080

[Patent Document 5]

U.S. Pat. No. 4,001,312

[Patent Document 6]

WO 01/25227

[Patent Document 7]

WO 94/27965

[Patent Document 8]

WO 98/46590

[Patent Document 9]

JP-A 6–263733

[Patent Document 10]

EP-A 487071

[Patent Document 11]

EP-A 378207

[Patent Document 12]

EP-A 30044

[Patent Document 13]

EP-A 560235

[Patent Document 14]

EP-A 567090

[-Patent Document 15]

EP-A 607864

[Patent Document 16]

EP-A 655451

DISCLOSURE OF INVENTION

An object of the present invention is to develop a preventive or atherapeutic agent for voiding disturbance, in particular, voidingdifficulty which has a higher therapeutic effect and convenience andless side effect, as compared with known compounds known to have voidingdisturbance therapeutic activity and concomitant use thereof. A furtherobject of the present invention is to develop a more effective methodfor assessing in vivo a therapeutic agent for voiding disturbanceaccompanied with benign prostatic hyperplasia.

In view of such the circumstances, the present inventors researched andinvestigated a new preventive or therapeutic agent for voidingdisturbance, in particular, voiding difficulty which has a high voidingefficiency and intensively studied and, as a result, found that aminecompounds of a peculiar chemical structure represented by the formula:

wherein meanings of respective symbols are as defined later, haveunexpectedly both of an acetylcholinesterase inhibitory action and an α1receptor antagonistic action based on its peculiar structure, exhibit anexcellent effect of improving the voiding function of the bladder (i.e.,effects of improving urine flow rate and voiding efficiency) and, at thesame time, unexpectedly have excellent effect of preventing or treatingvoiding disturbance, in particular, voiding difficulty without affectingvoiding pressure and blood pressure. In addition, the present inventorsfound that, upon in vivo assessment of these compounds, a therapeuticagent for voiding disturbance accompanied with benign prostatichyperplasia (BPH) can be unexpectedly assessed simply and precisely byapplying Pressure Flow Study to an α agonist (phenylephrine)-loadedguinea pigs. Base on these, the present invention was completed.

That is, the present invention relates to:

-   [1] a preventive or therapeutic agent for voiding disturbance, which    comprises a compound having both of an acetylcholinesterase    inhibitory action and an α1 antagonistic action,-   [2] the agent according to the above-mentioned [1], which comprises    a compound having both of an acetylcholinesterase inhibitory action    and an α1 antagonistic action represented by the formula:

-    wherein Ar represents an optionally condensed 5- or 6-membered    aromatic ring group and said aromatic ring group may have a    substituent, L represents a spacer having a main chain of 1 to 10 of    atoms which may have a substituent, or may form a ring with Ar, and    Y represents an amino group which may have a substituent or a    nitrogen-containing heterocyclic group which may have a substituent,    or a salt thereof or a prodrug thereof,-   [3] the agent according to the above-mentioned [2], wherein L is a    C₁₋₁₀ alkylene group which may have a substituent,-   [4] the agent according to the above-mentioned [1], which is a    preventive or therapeutic agent for voiding disturbance accompanied    with benign prostatic hyperplasia,-   [5] the agent according to the above-mentioned [1], wherein an IC₅₀    value of each of an acetylcholinesterase inhibitory action and an α1    antagonistic action of the compound is a ratio of about 1:100 to    about 100:1,-   [6] the agent according to the above-mentioned [1], wherein an IC₅₀    value of each of an acetylcholinesterase inhibitory action and an α1    antagonistic action of the compound is a ratio of about 1:1 to about    30:1,-   [7] the agent according to the above-mentioned [1], which does not    exhibit reduction of blood pressure at a dose exhibiting an effect    of improving urine flow rate,-   [8] the agent according to the above-mentioned [7], wherein a    reduction of blood pressure after administration is within about 10%    relative to that before administration at a dose in which a urine    flow rate after administration is improved by about 20% or more    relative to that before administration,-   [9 the agent according to the above-mentioned [1], which does not    exhibit reduction of blood pressure at, a dose exhibiting an effect    of improving voiding efficiency,-   [10] the agent according to the above-mentioned [9], wherein    reduction of blood pressure after administration is within about 10%    relative to that before administration at a dose that a voiding    efficiency after administration is improved by about 10% or more    relative to that before administration,-   [11] the agent according to the above-mentioned [1], wherein    orthostatic hypotension is not accompanied,-   [12] a method for preventing or treating voiding disturbance, which    comprises administering an effective amount of a compound having    both of an acetylcholinesterase inhibitory action and an α1    antagonistic action to a mammal,-   [13] use of a compound having both of an acetylcholinesterase    inhibitory action and an α1 antagonistic action for preparing a    preventive or therapeutic agent for voiding disturbance,-   [14] a compound represented by the formula:

-    wherein Ar₁ represents a di- to tetra-cyclic condensed benzene ring    group which may have a substituent, L₁ represents a C₄₋₆ alkylene    group which may have a substituent, L₂ represents a C₂₋₄ alkylene    group which may have a substituent, R represents a hydrogen atom or    a hydrocarbon group which may have a substituent, X represents a    bond, an oxygen atom or NR^(1a) (wherein R^(1a) represents a    hydrogen atom, a hydrocarbon group which may have a substituent, an    acyl group or a heterocyclic group which may have a substituent),    and Ar₂ represents an aromatic ring group which may have a    substituent, or Ar₂ and R, or Ar₂ and L₂ may link together to form a    ring, or a salt thereof,-   [15] the compound according to the above-mentioned [14] wherein Ar₁    is a group represented by the formula: wherein A ring represents a    benzene ring which may have a substituent, B ring represents a    homocyclic ring or a heterocyclic ring which may have a substituent,    one of C ring and D ring represents a heterocyclic ring which may    have a substituent, the other represents a 5- to 9-membered ring    which may have a substituent, and at least one ring of E ring, F    ring and G ring represents a heterocyclic ring which may have a    substituent and the other rings represent a 5- to 9-membered ring    which may have a substituent,-   [16] the compound according to the above-mentioned [14], wherein Ar₁    is a group represented by the formula:

-    wherein A ring is as defined above, Ba ring represents a homocyclic    ring or a heterocyclic ring which may have a substituent, C″ ring    and D″ ring represent a nitrogen-containing heterocyclic ring which    may have a substituent respectively, R¹ and R^(1′) represent a    hydrogen atom, a hydrocarbon group which may have a substituent, an    acyl group or a heterocyclic group which may have a substituent    respectively,-   [17] the compound according to the above-mentioned [16], wherein A    ring represents a benzene ring which may have 1 or 2 substituent(s)    selected from aminosulfonyl, mono- or di-C₁₋₆ alkylaminosulfonyl,    carbamoyl and mono- or di-C₁₋₆ alkyl-carbamoyl, Ba ring, C″ ring and    D″ ring may have 1 or 2 substituent(s) selected from C₁₋₆ alkyl,    C₁₋₆ alkyl-carbonylamino and C₁₋₆ alkylsulfonylamino, respectively,    and R¹ and R^(1′) represent (1) a hydrogen atom, (2) a C₁₋₆ alkyl    group or a C₇₋₁₆ aralkyl group, each of which may have 1 or 2    substituent(s) selected from hydroxy and C₁₋₆ alkoxy-carbonyl,    or (3) formula —(C═O)—R^(2′), —(C═O)—NR^(2′)R^(3′) or —SO₂R^(2′)    [wherein R^(2′) and R^(3′) represent hydrogen atom, optionally    halogenated C₁₋₆ alkyl or C₆₋₁₀ aryl, respectively],-   [18] the compound according to the above-mentioned [14], wherein R    is a hydrogen atom or a C₁₋₄ alkyl group,-   [19] the compound according to the above-mentioned [14], wherein L₁    is a C₄₋₅ alkylene group, and L₂ is a C₂₋₃ alkylene group which may    have phenyl, hydroxy or oxo,-   [20] the compound according to the above-mentioned [14], wherein Ar₂    is a C₆₋₁₀ aryl group or a 5- or 6-membered aromatic heterocyclic    group (optionally condensed with a benzene ring) containing 1 to 4    hetero atom(s) selected from a nitrogen atom, an oxygen atom and a    sulfur atom, each of which may have 1 to 3 substituent(s) selected    from halogen, nitro, hydroxy, optionally halogenated C₁₋₆ alkyl,    optionally halogenated C₁₋₆ alkoxy and aminosulfonyl,-   [21] the compound according to the above-mentioned [14], wherein the    ring formed by linking Ar₂ and R together is a ring represented by    the formula:

-    wherein, p and q represent an integer of 1 to 3, respectively, and    H ring represents a benzene ring which may have 1 to 3    substituent(s) selected from halogen, hydroxy, optionally    halogenated C₁₋₆ alkyl and optionally halogenated C₁₋₆ alkoxy,-    and the ring formed by linking Ar₂ and L₂ together is a ring    represented by the formula:

-    wherein, r represents an integer of 0 to 2, s represents an integer    of 1 to 3 and r+s an integer of 2 to 5, and H ring represents a    benzene ring which may have 1 to 3 substituents(s) selected from    halogen, hydroxy, optionally halogenated C₁₋₆ alkyl and optionally    halogenated C₁₋₆ alkoxy,-   [22] a compound represented by the formula:

-    wherein Ar₃ represents a benzimidazole ring group, a quinazoline    ring group, a 1,4-benzoxazine ring group or a tricyclic to    tetracyclic condensed benzene ring group, each of which may have a    substituent, L₃ represents a C₂₋₄ alkylene group which may have a    substituent, and other symbols are as defined above, or a salt    thereof,-   [23] the compound according to the above-mentioned [22], wherein Ar₃    is a group represented by the formula:

-    wherein A ring is as defined above, and C′ ring and D′ ring    represent a nitrogen-containing heterocyclic ring which may have a    substituent in addition to an oxo group, respectively,-   [24] the compound according to the above-mentioned [22], wherein L₃    is an ethylene group, L₂ is a C₂₋₃ alkylene group which may have    phenyl, hydroxy or oxo, and X is a bond or an oxygen atom,-   [25] the compound according to the above-mentioned [22], wherein Ar₂    is a C₆₋₁₀ aryl group or a 5- or 6-membered aromatic heterocyclic    group (optionally condensed with a benzene ring) containing 1 to 4    hetero atom(s) selected from a nitrogen atom, an oxygen atom and a    sulfur atom, each of which may have 1 to 3 substituent(s) selected    from halogen, nitro, hydroxy, optionally halogenated C₁₋₆ alkyl,    optionally halogenated C₁₋₆ alkoxy and aminosulfonyl, and the ring    formed by linking Ar₂ and L₂ together is a ring represented by the    formula:

-    wherein respective symbols are as defined above,-   [26] a compound represented by the formula:

-    wherein Ar₄ represents, a benzene ring group having 1 or 2    substituent(s) selected from aminosulfonyl, mono- or di-C₁₋₆    alkylaminosulfonyl, C₁₋₆ alkyl-carbonylamino and C₁₋₆    alkylsulfonylamino, and optionally further having 1 to 4    substituent(s), and the other respective symbols are as defined    above, or a salt thereof,-   [27] the compound according to the above-mentioned [26], wherein Ar₄    is a benzene ring group having 1 or 2 substituent(s) selected from    aminosulfonyl, mono- or di-C₁₋₆ alkylaminosulfonyl, C₁₋₆    alkyl-carbonylamino and C₁₋₆ alkylsulfonylamino, and optionally    further having 1 or 2 C₁₋₄ alkoxy(s), L₁ is a C₄₋₅ alkylene group,    L₂ is a C₂₋₃ alkylene group optionally having hydroxy or oxo, R is a    hydrogen atom or a C₁₋₄ alkyl group, X is a bond, and Ar₂ is a C₆₋₁₀    aryl group or a 5- or 6-membered aromatic heterocyclic group    (optionally condensed with a benzene ring) containing 1 to 4 hetero    atom(s) selected from a nitrogen atom, an oxygen atom and a sulfur    atom, each of which may have 1 to 3 substituent(s) selected from    halogen, nitro, hydroxy, optionally halogenated C₁₋₆ alkyl,    optionally halogenated C₁₋₆ alkoxy and aminosulfonyl,-   [28] a compound represented by the formula:

-    wherein n represents an integer of 1 or 2, L₄ represents a    C₃₋₅alkylene group which may have a substituent, and the other    respective symbols are as defined above, or a salt thereof,-   [29] the compound according to the above-mentioned [28], wherein R¹    and R^(1′) are a hydrogen atom or an optionally halogenated C₁₋₆    alkyl group, respectively, L₄ is a C₃₋₄ alkylene group, L₂ is a C₂₋₃    alkylene group which may have hydroxy or oxo, R is a hydrogen atom    or a C₁₋₄ alkyl group, X is a bond, and Ar₂ is a C₆₋₁₀ aryl group or    a 5- or 6-membered aromatic heterocyclic group (optionally condensed    with a benzene ring) containing 1 to 4 hetero atom(s) selected from    a nitrogen atom, an oxygen atom and a sulfur atom, each of which may    have 1 to 3 substituent(s) selected from halogen, nitro, hydroxy,    optionally halogenated C₁₋₆ alkyl, optionally halogenated C₁₋₆    alkoxy and aminosulfonyl,-   [30]    8-(5-[[2-(2-chlorophenyl)ethyl]amino]pentanoyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-one    or a salt thereof,-   5-[5-[[2-(2-chlorophenyl)ethyl](methyl)amino]pentanoyl]-1,3-dimethyl-1,3-dihydro-2H-benzimidazol-2-one    or a salt thereof,-   1,3-dimethyl-5-[5-({2-[2-(trifluoromethoxy)phenyl]ethyl}amino)pentanoyl]-1,3-dihydro-2H-benzimidazol-2-one    or a salt thereof,-   8-{5-[[2-(2-methoxyphenyl)ethyl](methyl)amino]pentanoyl}-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one    or a salt thereof,-   8-{5-[[2-(2-methoxyphenyl)ethyl](methyl)amino]pentanoyl}-1-methyl-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one    or a salt thereof,-   1,3-dimethyl-5-[5-({2-[2-(trifluoromethoxy)phenyl]ethyl}amino)pentanoyl]-1,3-dihydro-2H-benzimidazol-2-one    or a salt thereof,-   8-(5-{[2-(2-chlorophenyl)ethyl]amino}pentanoyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-one    or a salt thereof, or,-   5-(5-{[2-(2-chlorophenyl)ethyl]amino}pentanoyl)-1,3-dimethyl-1,3-dihydro-2H-benzimidazol-2-one    or a salt thereof,-   [31] a prodrug of the compound according to any one of the    above-mentioned [14], [22], [26] and [28] or a salt thereof,-   [32] a process for preparing the compound according to the    above-mentioned [14], which comprises reacting a compound    represented by the formula:

-    wherein Z₁ represents a leaving group, and the other respective    symbols are as defined above, or a salt thereof with a compound    represented by the formula:

-    wherein respective symbols are as defined above, or a salt thereof,-   [33] a process for preparing the compound represented by the    formula:

-    wherein Z₁ represents a leaving group, and the other respective    symbols are as defined above, or a salt thereof, which comprises    reacting a compound represented by the formula:    Ar₁—H-    wherein Ar₁ is as defined above, or a salt thereof with a compound    represented by the formula:

-    wherein Z₂ represents a leaving group, and Z₁ and L₁ are as defined    above, or a salt thereof,-   [34] the process according to the above-mentioned [33], wherein zinc    chloride is used as a catalyst and nitroalkane is used as a solvent,-   [35] a medicine comprising the compound according to any one of the    above-mentioned [14], [22], [26] and [28], or a salt thereof or a    prodrug thereof,-   [36] the medicine according to the above-mentioned [35], which is a    preventive or therapeutic agent for voiding disturbance,-   [37] the medicine according to the above-mentioned [35], which is a    preventive or therapeutic agent for voiding disturbance accompanied    with benign prostatic hyperplasia,-   [38] the medicine according to the above-mentioned [37], which is a    preventive or therapeutic agent for voiding disturbance due to    detrusor underactivity,-   [39] a method for preventing or treating voiding disturbance, which    comprises administering an effective amount of the compound    according to any one of the above-mentioned [14], [22], [26] and    [28] or a salt thereof or a prodrug thereof to a mammal,-   [40] use of the compound according to any one of the above-mentioned    [14], [22], [26] and [28] or a salt thereof or a prodrug thereof for    preparing a preventive or therapeutic agent for voiding disturbance,-   [41] a method for screening a compound having an voiding disturbance    preventing or treating effect by Pressure Flow Study, which    comprises using an animal model loaded with an α agonist,-   [42] the screening method according to the above-mentioned-   [41] wherein the α agonist is phenylephrine, and-   [43] a compound having an voiding disturbance preventing or treating    effect obtained by the screening method according to the    above-mentioned [41], or a salt thereof.

Among voiding disturbance, for example, voiding disturbance accompaniedwith benign prostatic hyperplasia is considered to result fromcompression of urethra by hypertrophied prostate, and functionalconstriction of prostate and urethra due to facilitation of sympatheticnervous system. In therapy thereof, administration of anacetylcholinesterase inhibitor alone, that is, enhancement of acontractile force of bladder muscle (detrusor muscle) in the state ofobstruction of urethra is at risk of causing high pressure voiding. Anα₁ receptor antagonist is a drug which improves functional contractionof prostate and urethra, and there is no risk of high pressure voiding.However, since the antagonist has basically antihypertensive action,side effect such as orthostatic hypotension is accompanied. On the otherhand, “a compound having both of an acetylcholinesterase inhibitoryaction and an α₁antagonistic action” (hereinafter, abbreviated asCompound A in some cases) used in the preventive or therapeutic agentfor voiding disturbance of the present invention relaxes urethra smoothmuscle and alleviates urethra resistance based on an α₁ antagonisticaction and, at the same time, enhances a contractile force of bladdermuscle (detrusor muscle) based on an acetylcholinesterase inhibitoryaction. Therefore, the preventive or therapeutic agent for voidingdisturbance containing Compound A of the present invention has a smallerrisk of high pressure voiding as compared with administration of anacetylcholinesterase inhibitor alone. In addition, as compared withadministration of an α₁ receptor antagonist alone, effects of improvingurine flow rate and a voiding efficiency are exhibited at a lower doseand, for this reason, influence on a blood pressure is smaller.

Then, the advantages of Compound A used in the present invention for“concomitant use therapy” of an α₁ receptor antagonist and anacetylcholinesterase inhibitor will be described. Generally, sincekinetics of a drug in the body differ from drug to drug, an elaboratesetting such as administration time, administration timing and the likeis required in order to obtain optimal effect in “concomitant usetherapy”. This becomes a burden on a patient to which a drug isadministered and a physician and, at the same time, increases thetrouble of compounding. In addition, recently, it has been found that,when drug interaction is caused in concomitant use of drugs, there is apossibility of potentiating side effect and death accident may happen insome cases. Therefore, it is necessary to pay a sufficient attention todrug interaction in “concomitant use therapy”. On the other hand, sincethe Compound A used in the present invention can be administered aloneto provide treatment, the burden on a patient to be administered and aphysician and the trouble of compounding can be alleviated and,moreover, there is no risk of drug interaction and, thus, it is morepreferable in terms of treatment and therapeutic economy as comparedwith “concomitant use therapy”.

Regarding an acetylcholinesterase inhibitory action possessed byCompound A used in the present invention, for example, in theafter-mentioned in vitro enzyme inhibition test 1a), an IC₅₀ value ispreferably about 1 μM or smaller, more preferably about 0.5 μM orsmaller.

In addition, an α₁ receptor is classified into three kinds of subtypesof α_(1A), α_(1B) and α_(1D) (Pharmacological Reviews, 1995, 47, 267),and it is known that about 70% of an α₁ receptor is an α_(1A) subtype inhuman prostate, and contraction of human prostate smooth muscle iscontrolled by an α_(1A) subtype (Journal of Urology, 1993, 150, 546;Molecular Pharmacology, 1994, 45, 703). Regarding an α₁ antagonisticaction possessed by Compound A, for example, in the after-mentioned invitro test 1b), an IC₅₀ value of α_(1A) receptor binding inhibitoryactivity is preferably about 1 μM or smaller, more preferably about 0.5μM or smaller.

Regarding the balance of both actions in Compound A, the ratio of IC₅₀values of an acetylcholinesterase inhibitory action and an α₁ (α_(1A))antagonistic action in an in vitro test is preferably, for example,about 1:1000 to about 1000:1, more preferably about 1:100 to about100:1, further more preferably about 1:20 to about 20:1. A compoundhaving a stronger α₁ antagonistic action of both actions is preferred,and examples thereof include a compound having a ratio of IC₅₀ values ofan acetylcholinesterase inhibitory action and an α₁ antagonistic actionof about 1:1 to about 30:1. The balance of both actions can be moreprecisely assessed by an in vivo test. Specifically, in a test 2described later, it is preferable that a voiding pressure is notinfluenced (a voiding pressure is not increased), effects of improving aurine flow rate and a voiding efficiency are exhibited (a urine flowrate after administration is improved by about 20% or more as comparedwith before administration, and a voiding efficiency afteradministration is improved by about 10% or more as compared with beforeadministration) and a blood pressure is not influenced at a doseexhibiting improving effects (reduction in a blood pressure afteradministration is within about 10% relative to before administration).

As Compound A used in the present invention, compounds having anymolecular structure may be used as far as they are a compound havingboth of an acetylcholinesterase inhibitory action and an α₁ antagonisticaction by itself. Inter alia, preferred is an amine compound in which ahydrogen atom of ammonia is substituted with a hydrocarbon group. Morepreferred are a primary amine compound, a secondary amine compound, anda tertiary amine compound.

Compound A used in the present invention include a compound which isconverted into a compound having both of an acetylcholinesteraseinhibitory action and an α₁ antagonistic action by converting into asalt, and a compound which is converted into a compound having both ofan acetylcholinesterase inhibitory action and an α₁ antagonistic actionby a reaction with an enzyme or gastric acid under the physiologicalconditions in a living body, such as a salt and a prodrug of Compounds(I), (Ia), (Ib), (Ic) and (Id) described later.

Specifically, the following compound is preferred.

A compound represented by the formula:

wherein Ar represents an optionally condensed 5- or 6-membered aromaticring group and said aromatic ring group may have a substituent, Lrepresents a spacer having a main chain of 1 to 10 atoms which may havea substituent, or may form a ring between Ar, and Y represents an aminogroup which may have a substituent or a nitrogen-containing heterocyclicring which may have a substituent (hereinafter, abbreviated as Compound(I) in some cases), or a salt thereof.

In the aforementioned formula, examples of the “substituent” in“represents an optionally condensed 5- or 6-membered aromatic ring groupand said aromatic ring group may have a substituent” represented by Arinclude (i) an optionally halogenated lower alkyl group, (ii) a halogenatom (e.g. fluoro, chloro, bromo, iodo etc.), (iii) a loweralkylenedioxy group (e.g. C₁₋₃ alkylenedioxy group such asmethylenedioxy, ethylenedioxy etc.), (iv) a nitro group, (v) a cyanogroup, (vi) a hydroxy group, (vii) an optionally halogenated loweralkoxy group, (viii) a cycloalkyl group (e.g. C₃₋₆ cycloalkyl group suchas cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc.), (ix) anoptionally halogenated lower alkylthio group, (x) an amino group, (xi) amono-lower alkylamino group (e.g. mono-C₁₋₆ alkylamino group such asmethylamino, ethylamino, propylamino etc.), (xii) a di-lower alkylaminogroup (e.g. di-C₁₋₆ alkylamino group such as dimethylamino, diethylaminoetc.), (xiii) a 5- to 7-membered cyclic amino group (e.g. 5- to7-membered cyclic amino group which may have 1 to 3 hetero atom(s)selected from a nitrogen atom, an oxygen atom and a sulfur atom inaddition to one nitrogen atom (e.g. 1-pyrrolidinyl, piperidino,1-piperazinyl, morpholino, thiomorpholino etc.) etc.), (xiv) a loweralkyl-carbonylamino group (e.g. C₁₋₆ alkyl-carbonylamino group such asacetylamino, propionylamino, butyrylamino etc.), (xv) a loweralkylsulfonylamino group (e.g. C₁₋₆ alkylsulfonylamino group such asmethylsulfonylamino, ethylsulfonylamino, propylsulfonylamino etc.),(xvi) a lower alkoxy-carbonyl group (e.g. C₁₋₆ alkoxy-carbonyl groupsuch as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isobutoxycarbonyl etc.), (xvii) a carboxy group, (xviii) a loweralkyl-carbonyl group (e.g. C₁₋₆ alkyl-carbonyl group such asmethylcarbonyl, ethylcarbonyl, butylcarbonyl etc.), (xix) acycloalkyl-carbonyl group (e.g. C₃₋₆ cycloalkyl-carbonyl group such ascyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl,cyclohexylcarbonyl etc.), (xx) a carbamoyl group, a thiocarbamoyl group,(xxi) a mono-lower alkyl-carbamoyl group (e.g. mono-C₁₋₆ alkyl-carbamoylgroup such as methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl,butylcarbamoyl etc.), (xxii) a di-lower alkyl-carbamoyl group (e.g.di-C₁₋₆ alkyl-carbamoyl group such as diethylcarbamoyl, dibutylcarbamoyletc.), (xxiii) a lower alkylsulfonyl group (e.g. C₁₋₆ alkylsulfonylgroup such as methylsulfonyl, ethylsulfonyl, propylsulfonyl etc.),(xxiv) a cycloalkylsulfonyl group (e.g. C₃₋₆ cycloalkylsulfonyl such ascyclopentylsulfonyl, cyclohexylsulfonyl etc.), (xxv) a phenyl group,(xxvi) a naphthyl group, (xxvii) a mono-phenyl-lower alkyl group (e.g.mono-phenyl-C₁₋₆ alkyl group such as benzyl, phenylethyl etc.), (xxviii)a di-phenyl-lower alkyl group (e.g. di-phenyl-C₁₋₆ alkyl group such asdiphenylmethyl, diphenylethyl etc.), (xxix) a mono-phenyl-loweralkyl-carbonyloxy group (e.g. mono-phenyl-C₁₋₆ alkyl-carbonyloxy groupsuch as phenylmethylcarbonyloxy, phenylethylcarbonyloxy etc.), (xxx) adi-phenyl-lower alkyl-carbonyloxy group (e.g. di-phenyl-C₁₋₆alkyl-carbonyloxy group such as diphenylmethylcarbonyloxy,diphenylethylcarbonyloxy etc.), (xxxi) a phenoxy group, (xxxii) amono-phenyl-lower alkyl-carbonyl group (e.g. mono-phenyl-C₁₋₆alkyl-carbonyl group such as phenylmethylcarbonyl, phenylethylcarbonyletc.), (xxxiii) a di-phenyl-lower alkyl-carbonyl group (e.g.di-phenyl-C₁₋₆ alkyl-carbonyl group such as diphenylmethylcarbonyl,diphenylethylcarbonyl etc.), (xxxiv) a benzoyl group, (xxxv) aphenoxycarbonyl group, (xxxvi) a phenyl-lower alkyl-carbamoyl group(e.g. phenyl-C₁₋₆ alkyl-carbamoyl group such as phenyl-methylcarbamoyl,phenyl-ethylcarbamoyl etc.), (xxxvii) a phenylcarbamoyl group, (xxxviii)a phenyl-lower alkyl-carbonylamino group (e.g. phenyl-C₁₋₆alkyl-carbonylamino group such as phenyl-methylcarbonylamino,phenyl-ethylcarbonylamino etc.), (xxxix) a phenyl-lower alkylamino group(e.g. phenyl-C₁₋₆ alkylamino group such as phenyl-methylamino,phenyl-ethylamino etc.), (xxxx) a phenyl-lower alkylsulfonyl group (e.g.phenyl-C₁₋₆ alkylsulfonyl group such as, phenyl-methylsulfonyl,phenyl-ethylsulfonyl etc.), (xxxxi) a phenylsulfonyl group, (xxxxii) aphenyl-lower alkylsulfinyl group (e.g. phenyl-C₁₋₆ alkylsulfinyl groupsuch as phenyl-methylsulfinyl, phenyl-ethylsulfinyl etc.), (xxxxiii) aphenyl-lower alkylsulfonylamino group (e.g. phenyl-C₁₋₆alkylsulfonylamino group such as phenyl-methylsulfonylamino,phenyl-ethylsulfonylamino etc.), (xxxxiv) a phenylsulfonylamino group,(xxxxv) a 5- to 7-membered cyclic amino-carbonyl group (e.g. 5- to7-membered cyclic amino-carbonyl group which may have 1 to 3 heteroatom(s) selected from a nitrogen atom, an oxygen atom and a sulfur atomin addition to one nitrogen atom (e.g. (1-pyrrolidinyl)carbonyl,piperidinocarbonyl, (1-piperazinyl)carbonyl, morpholinocarbonyl,thiomorpholinocarbonyl group etc.) etc.), (xxxxvi) an aminosulfonylgroup, (xxxxvii) a mono-lower alkylaminosulfonyl group (e.g. mono-C₁₋₆alkylaminosulfonyl group such as methylaminosulfonyl,ethylaminosulfonyl, propylaminosulfonyl, butylaminosulfonyl etc.),(xxxxviii) a di-lower alkylaminosulfonyl group (e.g. di-C₁₋₆alkylaminosulfonyl group such as diethylaminosulfonyl,dibutylaminosulfonyl etc.), (xxxxix) a 5- to 7-membered cyclicamino-sulfonyl group (e.g. 5- to 7-membered cyclic amino-sulfonyl groupwhich may have 1 to 3 hetero atom(s) selected from a nitrogen atom, anoxygen atom and a sulfur atom in addition to one nitrogen atom (e.g.(1-pyrrolidinyl)sulfonyl, piperidinosulfonyl, (1-piperazinyl)sulfonyl,morpholinosulfonyl, thiomorpholinosulfonyl group etc.), (xxxxx), anaminocarbonyloxy group, (xxxxxi) a mono-lower alkylaminocarbonyloxygroup (e.g. mono-C₁₋₆ alkylaminocarbonyloxy group such asmethylaminocarbonyloxy, ethylaminocarbonyloxy, propylaminocarbonyloxyetc.), (xxxxxii) a di-lower alkylaminocarbonyloxy group (e.g. di-C₁₋₆alkylaminocarbonyloxy group such as dimethylaminocarbonyloxy,diethylaminocarbonyloxy etc.) and (xxxxxiii) a 5- to 7-membered cyclicamino-carbonyloxy group (e.g. 5- to 7-membered cyclic amino-carbonyloxygroup which may have 1 to 3 hetero atom(s) selected from a nitrogenatom, an oxygen atom and a sulfur atom in addition to one nitrogen atom(e.g. (1-pyrrolidinyl)carbonyloxy, piperidinocarbonyloxy,(1-piperazinyl)carbonyloxy, morpholinocarbonyloxy,thiomorpholinocarbonyloxy group etc.) etc.) (the phenyl group moiety inphenyl group, naphthyl group, mono-phenyl-lower alkyl group,di-phenyl-lower alkyl group, mono-phenyl-lower alkyl-carbonyloxy group,di-phenyl-lower alkyl-carbonyloxy group, phenoxy group,mono-phenyl-lower alkyl-carbonyl group, di-phenyl-lower alkyl-carbonylgroup, benzoyl group, phenoxycarbonyl group, phenyl-loweralkyl-carbamoyl group, phenylcarbamoyl group, phenyl-loweralkyl-carbonylamino group, phenyl-lower alkylamino group, phenyl-loweralkylsulfonyl group, phenylsulfonyl group, phenyl-lower alkylsulfinylgroup, phenyl-lower alkylsulfonylamino group and phenylsulfonylaminogroup of the aforementioned (xxv) to (xxxxiv) may further have 1 to 4substituent(s) selected from, for example, a lower alkyl group (e.g.C₁₋₆ alkyl such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl,tert-butyl, pentyl, hexyl etc.), a lower alkoxy group (e.g. C₁₋₆ alkoxysuch as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,sec-butoxy, tert-butoxy etc.), a halogen atom (e.g. chloro, bromo, iodoetc.), a hydroxy group, a benzyloxy group, an amino group, a mono-loweralkylamino group (e.g. mono-C₁₋₆ alkylamino such as methylamino,ethylamino, propylamino etc.), a di-lower alkylamino group (e.g. di-C₁₋₆alkylamino such as dimethylamino, diethylamino etc.), a nitro group, alower alkyl-carbonyl group (e.g. C₁₋₆ alkyl-carbonyl such asmethylcarbonyl, ethylcarbonyl, butylcarbonyl etc.), and a benzoylgroup).

The “optionally condensed 5-or 6-membered aromatic ring group”represented by Ar may have 1 to 4, preferably 1 or 2 of thesesubstituent(s) of (i) to (xxxxxiii).

Examples of the above-mentioned “optionally halogenated lower alkylgroup” include a lower alkyl group (e.g. C₁₋₆ alkyl group such asmethyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl,hexyl etc.) which may have 1 to 3 halogen atom(s) (e.g. chloro, bromo,iodo, etc.), specifically, methyl, chloromethyl, difluoromethyl,trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl,2,2,2-trifluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl, butyl,4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl,isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl, and6,6,6-trifluorohexyl.

Examples of the above-mentioned “optionally halogenated lower alkoxygroup” include a lower alkoxy group (e.g. C₁₋₆ alkoxy group such asmethoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy,tert-butoxy etc.) which may have 1 to 3 halogen atom(s) (e.g. chloro,bromo, iodo etc.), specifically, methoxy, difluoromethoxy,trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy,butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy, andhexyloxy.

Examples of the above-mentioned “optionally halogenated lower alkylthiogroup” include a lower alkylthio group (e.g. C₁₋₆ alkylthio group suchas methylthio, ethylthio, propylthio, isopropylthio, butylthio,isobutylthio, sec-butylthio, tert-butylthio etc.) which may have 1 to 3halogen atom(s) (e.g. chloro, bromo, iodo etc.), specifically,methylthio, difluoromethylthio, trifluoromethylthio, ethylthio,propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio,isobutylthio, sec-butylthio, tert-butylthio, pentylthio, and hexylthio.

Preferable examples of the “substituent” in the “represents anoptionally condensed 5- or 6-membered aromatic ring group and saidaromatic ring group may have a substituent” include (i) an amino group,(ii) a mono-lower alkylamino group (e.g. mono-C₁₋₆ alkylamino group suchas methylamino, ethylamino, propylamino etc.), (iii) a di-loweralkylamino group (e.g. di-C₁₋₆ alkylamino group such as dimethylamino,diethylamino etc.), (iv) a 5- to 7-membered cyclic amino group which mayhave 1 to 3 hetero atom(s) selected from a nitrogen atom, an oxygen atomand sulfur atom in addition to one nitrogen atom (e.g. 1-pyrrolidinyl,piperidino, 1-piperazinyl, morpholino, thiomorpholino etc.), (v) a loweralkyl-carbonylamino group (e.g. C₁₋₆ alkyl-carbonylamino group such asacetylamino, propionylamino, butyrylamino etc.), (vi) a loweralkylsulfonylamino group (e.g. C₁₋₆ alkylsulfonylamino group such asmethylsulfonylamino, ethylsulfonylamino, propylsulfonylamino etc.),(vii) a phenyl-lower alkylamino (e.g. phenyl-C₁₋₆ alkylamino such asphenyl-methylamino, phenyl-ethylamino etc.), (viii) a phenyl-loweralkylsulfonylamino group (e.g. phenyl-C₁₋₆ alkyl-sulfonylamino groupsuch as phenyl-methylsulfonylamino, phenyl-ethylsulfonylamino etc.),(ix) a phenylsulfonylamino, (x) a halogen atom (e.g. fluoro, chloroetc.), (xi) an optionally halogenated lower alkyl group, (e.g. methyl,ethyl, isopropyl, tert-butyl, trifluoromethyl etc.), (xii) an optionallyhalogenated lower alkoxy group (e.g. methoxy, ethoxy, isopropoxy,tert-butoxy, trifluoromethoxy etc.), (xiii) an aminosulfonyl group,(xiv) a mono-lower alkylaminosulfonyl group (e.g. mono-C₁₋₆alkylaminosulfonyl group such as methylaminosulfonyl,ethylaminosulfonyl, propylaminosulfonyl, butylaminosulfonyl etc.), (xv)a di-lower alkylaminosulfonyl group (e.g. di-C₁₋₆ alkylaminosulfonylgroup such as diethylaminosulfonyl, dibutylaminosulfonyl etc.), (xvi) acarbamoyl group, (xvii) a mono-lower alkyl-carbamoyl group (e.g.mono-C₁₋₆ alkyl-carbamoyl group such as methylcarbamoyl, ethylcarbamoyl,propylcarbamoyl, butylcarbamoyl etc.), and (xviii) a di-loweralkyl-carbamoyl group (e.g. di-C₁₋₆ alkyl-carbamoyl group such asdiethylcarbamoyl, dibutylcarbamoyl etc.). Particularly, a di-loweralkylamino group (e.g. di-C₁₋₆ alkylamino group such as dimethylamino,diethylamino etc.), a 5- to 7-membered cyclic amino group which may have1 to 3 hetero atom(s) selected from a nitrogen atom, an oxygen atom anda sulfur atom in addition to one nitrogen atom (e.g. 1-pyrrolidinyl,piperidino, 1-piperazinyl, morpholino, thiomorpholino etc.), anoptionally halogenated lower alkoxy group (e.g. methoxy, ethoxy,isopropoxy, tert-butoxy, trifluoromethoxy etc.), an aminosulfonyl group,a mono-lower alkylaminosulfonyl group (e.g. mono-C₁₋₆ alkylaminosulfonylgroup such as methylaminosulfonyl, ethylaminosulfonyl,propylaminosulfonyl, butylaminosulfonyl etc.), a di-loweralkyl-aminosulfonyl group (e.g. di-C₁₋₆ alkylaminosulfonyl group such asdiethylaminosulfonyl, dibutylaminosulfonyl etc.), a carbamoyl group, amono-lower alkyl-carbamoyl group (e.g. mono-C₁₋₆ alkyl-carbamoyl groupsuch as methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, butylcarbamoyletc.), and a di-lower alkyl-carbamoyl group (e.g. di-C₁₋₆alkyl-carbamoyl group such as diethylcarbamoyl, dibutylcarbamoyl etc.)are preferred.

Examples of the “5-or 6-membered aromatic ring group” in the “optionallycondensed 5- or 6-membered aromatic ring group” represented by Arinclude a phenyl group (benzene ring group), and a 5- or 6-memberedaromatic heterocyclic group.

Examples of the “5- or 6-membered aromatic heterocyclic group” include5- or 6-membered aromatic heterocyclic groups containing 1 or more (e.g.1 to 3) hetero atom(s) selected from a nitrogen atom, a sulfur atom andan oxygen atom in addition to carbon atoms. Specific examples includethienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl,isothiazolyl, oxazolyl, isooxazolyl, pyridyl, pyrazinyl, pyrimidinyl,pyridazinyl, oxadiazolyl, thiadiazolyl, and furazanyl.

When the “5- or 6-membered aromatic ring group” in the “optionallycondensed 5- or 6-membered aromatic ring group” represented by Ar is,for example, “a phenyl group which may have a substituent”, examples ofcondensing of the “phenyl group” include:

-   (a) the case where the phenyl group is condensed with a monocyclic    homocyclic ring or heterocyclic ring, which may have a substituent,-   (b) the case where the phenyl group is condensed with a dicyclic    homocyclic ring or heterocyclic ring, which may have a substituent,    or is condensed with two same or different monocyclic homocyclic    rings or heterocyclic rings, and-   (c) the case where the phenyl group is condensed with a tricyclic    homocyclic ring or heterocyclic ring which may have a substituent.

Examples of the case where a phenyl group in the “optionally condensedphenyl group, and said phenyl group may have a substituent” of theabove-mentioned (a) is condensed with a monocyclic homocyclic ring orheterocyclic ring include a group represented by the formula:

wherein A ring represents a benzene ring which may have a substituent,and B ring represents a homocyclic ring or a heterocyclic ring which mayhave a substituent.

Examples of a substituent of A ring include the aforementioned“substituents” of the “optionally condensed 5 or 6-membered aromaticring group” represented by Ar, and the number of substituent(s) is 1 to3.

Examples of the “homocyclic ring” in the “homocyclic ring which may havea substituent” represented by B ring include 5- to 9-memberedcarbocyclic rings (e.g. benzene, cyclopentane, cyclopentene,cyclohexane, cyclohexene, cyclohexadiene, cycloheptane, cycloheptene,cycloheptadiene etc.).

Examples of the “heterocyclic ring” in the “heterocyclic ring which mayhave a substituent” represented by B ring include 4- to 14-membered(preferably 5- to 9-membered) aromatic or non-aromatic heterocyclicrings containing 1 to 4 hetero atom(s) selected from a nitrogen atom, anoxygen atom and a sulfur atom. Specific examples include pyridine,pyrazine, pyrimidine, imidazole, furan, thiophen, dihydropyridine,diazepine, oxazepine, pyrrolidine, piperidine, hexamethyleneimine,heptamethyleneimine, tetrahydrofuran, tetrahydropyran, 1,4-dioxane,piperazine, homopiperazine, tetrahydrooxazepine, morpholine,thiomorpholine, pyrrole, pyrazole, 1,2,3-triazole, oxazole, oxazolidine,thiazole, thiazolidine, thiadiazolidine, thiadiazinone, isoxazole,imidazoline, imidazolidine, and hexahydropyrimidine. Among them, 5- to9-membered non-aromatic heterocyclic rings containing one hetero atom orthe same or different two hetero atoms (e.g. pyrrolidine, piperidine,hexamethyleneimine, heptamethyleneimine, tetrahydrofuran,tetrahydropyran, 1,4-dioxane, piperazine, homopiperazine,tetrahydrooxazepine, morpholine, thiomorpholine, imidazoline,thiadiazolidine, thiadiazinone, imidazolidine, hexahydropyrimidine etc.)are preferable. In particular, (1) a non-aromatic heterocyclic ringcontaining one hetero atom selected from a nitrogen atom, an oxygen atomand a sulfur atom, and (2) a non-aromatic heterocyclic ring containingone nitrogen atom and one hetero atom selected from a nitrogen atom, anoxygen atom and a sulfur atom are preferable.

As the “substituent” in the “homocyclic ring or heterocyclic ring whichmay have a substituent” represented by B ring, for example, 1 to 5selected from (i) a halogen atom (e.g. fluoro, chloro, bromo, iodoetc.), (ii) a nitro group, (iii) a cyano group, (iv) an oxo group, (v) ahydroxy group, (vi) a lower alkyl group (e.g. C₁₋₆ alkyl group such asmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyletc.), (vii), a lower alkoxy group (e.g. C₁₋₆ alkoxy group such asmethoxy, ethoxy, propyloxy, isopropyloxy, butyloxy etc.), (viii) a loweralkylthio group (e.g. C₁₋₆ alkylthio group such as methylthio,ethylthio, propylthio etc.), (ix) an amino group, (x) a mono-loweralkylamino group (e.g. mono-C₁₋₆ alkylamino group such as methylamino,ethylamino, propylamino etc.), (xi) a di-lower alkylamino group (e.g.di-C₁₋₆ alkylamino group such as dimethylamino, diethylamino etc.),(xii) a 5- to 7-membered cyclic amino group which may have 1 to 3 heteroatom(s) selected from a nitrogen atom, an oxygen atom and a sulfur atomin addition to carbon atoms and one nitrogen atom (e.g. 1-pyrrolidinyl,piperidino, 1-piperazinyl, morpholino, thiomorpholino etc.), (xiii) alower alkyl-carbonylamino group (e.g. C₁₋₆ alkyl-carbonylamino groupsuch as acetylamino, propionylamino, butyrylamino etc.), (xiv) a loweralkylsulfonylamino group (e.g. C₁₋₆ alkylsulfonylamino group such asmethylsulfonylamino, ethylsulfonylamino etc.), (xv) a loweralkoxy-carbonyl group (e.g. C₁₋₆ alkoxy-carbonyl group such asmethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl etc.), (xvi) a carboxygroup, (xvii) a lower alkylcarbonyl group (e.g. C₁₋₆ alkyl-carbonylgroup such as methylcarbonyl, ethylcarbonyl, propylcarbonyl etc.),(xviii) a carbamoyl group, (xix) a mono-lower alkylcarbamoyl group (e.g.mono-C₁₋₆ alkyl-carbamoyl group such as methylcarbamoyl, ethylcarbamoyletc.), (xx) a di-lower alkylcarbamoyl group (e.g. di-C₁₋₆alkyl-carbamoyl group such as dimethylcarbamoyl, diethylcarbamoyl etc.),(xxi) a lower alkylsulfonyl group (e.g. C₁₋₆ alkylsulfonyl group such asmethylsulfonyl, ethylsulfonyl, propylsulfonyl etc.), (xxii) anaminosulfonyl group, (xxiii) a mono-lower alkylaminosulfonyl group (e.g.mono-C₁₋₆ alkyl-aminosulfonyl group such as methylaminosulfonyl,ethylaminosulfonyl etc.), and (xxiv) a di-lower alkylaminosulfonyl group(e.g. di-C₁₋₆ alkyl-aminosulfonyl group such as dimethylaminosulfonyl,diethylaminosulfonyl etc.) are used. Inter alia, an oxo group, and alower alkyl group (e.g. C₁₋₆ alkyl group such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, tert-butyl, sec-butyl etc.) are preferable.An oxo group, a C₁₋₆ alkyl group, a C₁₋₆ alkyl-carbonylamino group and aC₁₋₆ alkylsulfonylamino group are particularly preferred.

When B ring has a nitrogen atom in the ring, for example, the B ring mayhave a group represented by the formula:>N—R¹wherein R¹ represents a hydrogen atom, a hydrocarbon group which mayhave a substituent, an acyl group, or a heterocyclic group which mayhave a substituent, in the ring. Further, the B ring may have 1 to 3 ofthe aforementioned substituents (i) to (xxiv).

The “hydrocarbon group” in the “hydrocarbon group which may have asubstituent” represented by R¹ represents a group obtained by removingone hydrogen atom from a hydrocarbon compound, and examples thereofinclude the following alkyl group, alkenyl group, alkynyl group,cycloalkyl group, aryl group, and aralkyl group, and a combinationthereof. Among them, C₁₋₁₆ hydrocarbon groups are preferred.

-   (1) Alkyl group (e.g. C₁₋₆ alkyl group such as methyl, ethyl,    propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl,    hexyl etc.)-   (2) Alkenyl group (e.g. C₂₋₆ alkenyl group such as vinyl, allyl,    isopropenyl, butenyl, isobutenyl, sec-butenyl etc.)-   (3) Alkynyl group (e.g. C₂₋₆ alkynyl group such as propargyl,    ethynyl, butynyl, 1-hexynyl etc.)-   (4) Cycloalkyl group (e.g. C₃₋₆ cycloalkyl group such as    cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc.)-   (5) Cross-linked cyclic lower saturated hydrocarbon group (e.g.    cross-linked cyclic C₈₋₁₄ saturated hydrocarbon group such as    bicyclo[3.2.1]oct-2-yl, bicyclo[3.3.1]non-2-yl, and adamantan-1-yl    etc.)-   (6) Aryl group (e.g. C₆₋₁₄ aryl group such as phenyl, 1-naphthyl,    2-naphthyl, biphenyl, 2-indenyl, 2-anthryl etc., preferably phenyl    group)-   (7) Aralkyl group (e.g. C₇₋₁₆ aralkyl group such as phenyl-C₁₋₁₀    alkyl such as benzyl, phenylethyl, phenylpropyl, phenylbutyl,    phenylpentyl, phenylhexyl etc.; naphthyl-C₁₋₆ alkyl such as    α-naphthylmethyl; diphenyl-C₁₋₃ alkyl such as diphenylmethyl,    diphenylethyl etc.)-   (8) Aryl-alkenyl group (e.g. C₆₋₁₄ aryl-C₂₋₁₂ alkenyl group such as    phenyl-C₂₋₁₂ alkenyl such as styryl, cinnamyl, 4-phenyl-2-butenyl,    4-phenyl-2-butenyl etc.)-   (9) Aryl-C₂₋₁₂ alkynyl group (e.g. C₆₋₁₄ aryl-C₂₋₁₂ alkynyl group    such as phenyl-C₂₋₁₂ alkynyl such as phenylethynyl,    3-phenyl-2-propynyl, 3-phenyl-1-propynyl etc.)-   (10) Cycloalkyl-alkyl group (e.g. C₃₋₇ cycloalkyl-C₁₋₆ alkyl group    such as cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,    cyclohexylmethyl, cycloheptylmethyl, cyclopropylethyl,    cyclobutylethyl, cyclopentylethyl, cyclohexylethyl,    cycloheptylethyl, cyclopropylpropyl, cyclobutylpropyl,    cyclopentylpropyl, cyclohexylpropyl, cycloheptylpropyl,    cyclopropylbutyl, cyclobutylbutyl, cyclopentylbutyl,    cyclohexylbutyl, cycloheptylbutyl, cyclopropylpentyl,    cyclobutylpentyl, cyclopentylpentyl, cyclohexylpentyl,    cycloheptylpentyl, cyclopropylhexyl, cyclobutylhexyl,    cyclopentylhexyl, cyclohexylhexyl etc.)-   (11) Aryl-aryl-C₁₋₁₀ alkyl group (e.g. biphenylmethyl, biphenylethyl    etc.)

Preferable examples of the “hydrocarbon group” in the “hydrocarbon groupwhich may have a substituent” represented by R¹ include a C₁₋₆ alkylgroup, a C₃₋₆ cycloalkyl group, and a C₇₋₁₆ aralkyl group. Morepreferred is a C₇₋₁₀ aralkyl group (e.g. phenyl-C₁₋₄ alkyl such asbenzyl, phenylethyl, phenylpropyl, etc.).

Examples of the “substituent” in the “hydrocarbon group which may have asubstituent” represented by R¹ include 1 to 5 (preferably 1 to 3)selected from (i) a halogen atom (e.g. fluoro, chloro, bromo, iodoetc.), (ii) a nitro group, (iii) a cyano group, (iv) an oxo group, (v) ahydroxy group, (vi) an optionally halogenated lower (C₁₋₆)alkyl group,(vii) an optionally halogenated lower (C₁₋₆)alkoxy group, (viii) anoptionally halogenated lower (C₁₋₆)alkylthio group, (ix) an amino group,(x) a mono-lower alkylamino group (e.g. mono-C₁₋₆ alkylamino group suchas methylamino, ethylamino, propylamino etc.), (xi) a di-loweralkylamino group (e.g. di-C₁₋₆ alkylamino group such as dimethylamino,diethylamino etc.), (xii) a 5- to 7-membered cyclic amino group whichmay have 1 to 3 hetero atom(s) selected from a nitrogen atom, an oxygenatom and a sulfur atom in addition to carbon atoms and one nitrogen atom(e.g. 1-pyrrolidinyl, piperidino, 1-piperazinyl, morpholino,thiomorpholino etc.), (xiii) a lower alkyl-carbonylamino group (e.g.C₁₋₆ alkyl-carbonylamino group such as acetylamino, propionylamino,butyrylamino etc.), (xiv) a lower alkylsulfonylamino group (e.g. C₁₋₆alkyl-sulfonylamino group such as methylsulfonylamino,ethylsulfonylamino etc.), (xv) a lower alkoxy-carbonyl group (e.g. C₁₋₆alkoxy-carbonyl group such as methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl etc.), (xvi) a carboxy group, (xvii) a loweralkyl-carbonyl group (e.g. C₁₋₆ alkyl-carbonyl group such asmethylcarbonyl, ethylcarbonyl, propylcarbonyl etc.), (xviii) a carbamoylgroup, a thiocarbamoyl group, (xix) a mono-lower alkyl-carbamoyl group(e.g. mono-C₁₋₆ alkyl-carbamoyl group such as methylcarbamoyl,ethylcarbamoyl etc.), (xx) a di-lower alkyl-carbamoyl group (e.g.di-C₁₋₆ alkyl-carbamoyl group such as dimethylcarbamoyl,diethylcarbamoyl etc.), (xxi) a lower alkylsulfonyl group (e.g. C₁₋₆alkylsulfonyl group such as methylsulfonyl, ethylsulfonyl,propylsulfonyl etc.), (xxii) a lower alkoxy-carbonyl-lower alkyl group(e.g. C₁₋₆ alkyl-carbonyl-C₁₋₆ alkyl group such asmethoxycarbonylmethyl, ethoxycarbonylmethyl, tert-butoxycarbonylmethyl,methoxycarbonylethyl, methoxycarbonylmethyl,methoxycarbonyl(dimethyl)methyl, ethoxycarbonyl(dimethyl)methyl,tert-butoxycarbonyl(dimethyl)methyl etc.), (xxiii) a carboxy-lower alkylgroup (e.g. carboxy-C₁₋₆ alkyl group such as carboxylmethyl,carboxylethyl, carboxyl(dimethyl)methyl etc.), (xxiv) a heterocyclicgroup which may have a substituent, (xxv) a C₆₋₁₄ aryl group (e.g.phenyl, naphthyl etc.), (xxvi) a C₇₋₁₆ aralkyl group (e.g. benzyl etc.),(xxvii) a ureido group which may have a substituent (e.g. C₁₋₄ alkyl,halogenoC₁₋₄ alkyl, C₆₋₁₀ aryl, halogenoC₆₋₁₀ aryl, C₁₋₄ alkyl-C₆₋₁₀aryl, halogenoC₁₋₄ alkyl-C₆₋₁₀ aryl, C₁₋₄ alkoxy-C₆₋₁₀ aryl, benzyletc.) (e.g. ureido, 3-methylureido, 3-ethylureido, 3-phenylureido,3-(4-fluorophenyl)ureido, 3-(2-methylphenyl)ureido,3-(4-methoxyphenyl)ureido, 3-(2,4-difluorophenyl)ureido,3-[3,5-bis(trifluoromethyl)phenyl]ureido, 3-benzylureido,3-(1-naphthyl)ureido, 3-(2-biphenylyl)ureido etc.), (xxviii) athioureido group which may have a substituent (e.g. C₁₋₄ alkyl,halogenoC₁₋₄ alkyl, C₆₋₁₀ aryl, halogenoC₆₋₁₀ aryl, C₁₋₄ alkyl-C₆₋₁₀aryl, halogenoC₁₋₄ alkyl-C₆₋₁₀ aryl, C₁₋₄ alkoxy-C₆₋₁₀ aryl, benzyletc.) (e.g. thioureido, 3-methylthioureido, 3-ethylthioureido,3-phenylthioureido, 3-(4-fluorophenyl)thioureido,3-(4-methylphenyl)thioureido, 3-(4-methoxyphenyl)thioureido,3-(2,4-dichlorophenyl)thioureido, 3-benzylthioureido,3-(1-naphthyl)thioureido etc.), (xxix) an amidino group which may have asubstituent (e.g. 1 to 2 selected from C₁₋₄ alkyl, C₆₋₁₀ aryl,nitro-C₆₋₁₀ aryl etc.) (e.g. amidino, N¹-methylamidino, N¹-ethylamidino,N¹-phenylamidino, N¹,N¹-dimethylamidino, N¹,N²-dimethylamidino,N¹-methyl-N¹-ethylamidino, N¹,N¹-diethylamidino,N¹-methyl-N¹-phenylamidino, N¹,N¹-di(4-nitrophenyl)amidino etc.), (xxx)a guanidino group which may have a substituent (e.g. 1 to 2 selectedfrom C₁₋₄ alkyl, C₆₋₁₀ aryl, nitro-C₆₋₁₀ aryl etc.)(e.g. guanidino,3-methylguanidino, 3,3-dimethylguanidino, 3,3-diethylguanidino etc.),(xxxi) a cyclic aminocarbonyl group which may have a substituent (e.g.C₁₋₄ alkyl, halogenoC₁₋₄ alkyl, C₆₋₁₀ aryl, halogenoC₆₋₁₀ aryl, C₁₋₄alkyl-C₆₋₁₀ aryl, halogenoC₁₋₄ alkyl-C₆₋₁₀ aryl, C₁₋₄ alkoxy-C₆₋₁₀ aryl,nitro-C₆₋₁₀ aryl, benzyl, halogenobenzyl, benzoyl, halogenobenzoyl etc.)(e.g. (1-pyrrolidinyl)carbonyl, piperidinocarbonyl,(4-methylpiperidino)carbonyl, (4-phenylpiperidino)carbonyl,(4-benzylpiperidino)carbonyl, (4-benzoylpiperidino)carbonyl,[4-(4-fluorobenzoyl)piperidino]carbonyl,(4-methyl-1-piperazinyl)carbonyl, (4-phenyl-1-piperazinyl)carbonyl,[4-(4-nitrophenyl)-1-piperazinyl]carbonyl,(4-benzyl-1-piperazinyl)carbonyl, morpholinocarbonyl,thiomorpholinocarbonyl etc.), (xxxii) an aminothiocarbonyl group whichmay have a substituent (e.g. 1 to 2 selected from C₁₋₄ alkyl, C₆₋₁₀ aryletc.) (e.g. aminothiocarbonyl, methylaminothiocarbonyl,dimethylaminothiocarbonyl etc.), (xxxiii) an aminosulfonyl group whichmay have a substituent (e.g. 1 to 2 selected from C₁₋₄ alkyl, C₆₋₁₀ aryletc.) (e.g. aminosulfonyl, methylaminosulfonyl, dimethylaminosulfonyletc.), (xxxiv) a phenylsulfonylamino group which may have a substituent(e.g. 1 to 2 selected from halogen atom, C₁₋₄ alkyl, halogenoC₁₋₄ alkyl,C₁₋₄ alkoxy, nitro, C₁₋₄ alkyl-carbonylamino etc.) (e.g.phenylsulfonylamino, (4-methylphenyl)sulfonylamino,(4-chlorophenyl)sulfonylamino, (2,5-dichlorophenyl)sulfonylamino,(4-methoxyphenyl)sulfonylamino, (4-acetylaminophenyl)sulfonylamino,(4-nitrophenyl)phenylsulfonylamino etc.), (xxxv) a sulfo group, (xxxvi)a sulfino group, (xxxvii) a sulfeno group, (xxxviii) a C₁₋₆ alkylsulfogroup (e.g. methylsulfo, ethylsulfo, propylsulfo etc.), (xxxix) a C₁₋₆alkylsulfino group (e.g. methylsulfino, ethylsulfino, propylsulfinoetc.), (xxxx) a C₁₋₆ alkylsulfeno group (e.g. methylsulfeno,ethylsulfeno, propylsulfeno etc.), (xxxxi) a phosphono group, (xxxxii) adi-C₁₋₆ alkoxyphosphoryl group (e.g. dimethoxyphosphoryl,diethoxyphosphoryl, dipropoxyphosphoryl etc.), (xxxxiii) anaminocarbonyloxy group, (xxxxxi) a mono-lower alkylaminocarbonyloxygroup (e.g. mono-C₁₋₆ alkylaminocarbonyloxy group such asmethylaminocarbonyloxy, ethylaminocarbonyloxy, propylaminocarbonyloxyetc.), (xxxxxii) a di-lower alkylaminocarbonyloxy group (e.g. di-C₁₋₆alkylaminocarbonyloxy group such as dimethylaminocarbonyloxy,diethylaminocarbonyloxy etc.) and (xxxxxiii) a 5- to 7-membered cyclicamino-carbonyloxy group (e.g. 5- to 7-membered cyclic amino-carbonyloxygroup which may have 1 to 3 hetero atom(s) selected from a nitrogenatom, an oxygen atom and a sulfur atom in addition to one nitrogen atom(e.g. (1-pyrrolidinyl)carbonyloxy, piperidinocarbonyloxy,(1-piperazinyl)carbonyloxy, morpholinocarbonyloxy,thiomorpholinocarbonyloxy group etc.) etc.).

Among them, preferred are a halogen atom, an optionally halogenated C₁₋₆alkyl group, an optionally halogenated C₁₋₆ alkoxy group, a hydroxygroup, a nitro group, a cyano group, a carboxy group, a C₁₋₆alkoxy-carbonyl group, a carbamoyl group, an aminothiocarbonyl group, amono-C₁₋₆ alkyl-carbamoyl group, a di-C₁₋₆ alkyl-carbamoyl group, anamino group, a mono-C₁₋₆ alkylamino group, a di-C₁₋₆ alkylamino group, a5- to 7-membered cyclic amino group, a C₁₋₆ alkyl-carbonylamino group,an aminosulfonyl group, a mono-C₁₋₆ alkylaminosulfonyl group, a di-C₁₋₆alkylaminosulfonyl group, a phenylsulfonylamino group, and a C₁₋₆alkylsulfonylamino group.

As the “heterocyclic group” in the aforementioned “(xxiv) heterocyclicgroup which may have a substituent”, for example, groups obtained byremoving one hydrogen atom from a 5- to 14-membered (monocyclic or di-to tetra-cyclic) heterocyclic ring containing 1 to 6 (preferably 1 to 4)hetero atom(s) selected from a nitrogen atom, an oxygen atom and asulfur atom are used.

Examples of the monocyclic heterocyclic group include groups obtained byremoving one hydrogen atom from monocyclic heterocyclic rings such aspyridine, pyrazine, pyrimidine, imidazole, furan, thiophen,dihydropyridine, diazepine, oxazepine, pyrrolidine, piperidine,hexamethyleneimine, heptamethylemeimine, tetrahydrofuran, piperazine,homopiperazine, tetrahydrooxazepine, morpholine, thiomorpholine,pyrrole, pyrazole, 1,2,3-triazole, oxazole, oxazolidine, thiazole,thiazolidine, isoxazole, imidazoline, triazole, thiadiazole, oxadiazole,oxathiadiazole, triazine, and tetrazole.

As the dicyclic heterocyclic ring, for example, groups obtained byremoving one hydrogen atom from dicyclic heterocyclic rings such asindole, dihydroindole, isoindole, dihydroisoindole, benzofuran,dihydrobenzofuran, benzimidazole, benzoxazole, benzisoxazole,benzothiazole, indazole, quinoline, tetrahydroquinoline, isoquinoline,tetrahydroisoquinoline, tetrahydro-1H-1-benzazepine,tetrahydro-1H-2-benzazepine, tetrahydro-1H-3-benzazepine,tetrahydrobenzoxazepine, quinazoline, tetrahydroquinazoline,quinoxaline, tetrahydroquinoxaline, benzodioxane, benzodioxol,benzothiazine, and imidazopyridine are used.

Examples of the tri- or tetra-cyclic heterocyclic group include groupsobtained by removing one hydrogen atom from tri- or tetra-cyclicheterocyclic rings such as acridine, tetrahydroacridine,pyrroloquinoline, pyrroloindole, cyclopentindole, andisoindolobenzazepine.

As the “heterocyclic group”, groups obtained by removing one hydrogenatom from monocyclic or dicyclic heterocyclic rings are preferred.

Examples of the “substituent” in the “heterocyclic group which may havea substituent” include “substituents” for the “homocyclic ring orheterocyclic ring which may have a substituent” represented by theabove-mentioned B ring, and the number of substituent(s) is 1 to 5.

Preferable examples of the “hydrocarbon group which may have asubstituent” represented by R¹ include a C₇₋₁₆ aralkyl group (preferablybenzyl etc.) which may have 1 to 5 substituent(s) selected from halogenatom, C₁₋₆ alkyl, C₁₋₆ alkoxy, nitro, cyano, carbamoyl, mono-C₁₋₆alkyl-carbamoyl, di-C₁₋₆ alkyl-carbamoyl, aminosulfonyl, mono-C₁₋₆alkylaminosulfonyl, di-C₁₋₆ alkylaminosulfonyl and hydroxy.

Examples of the “acyl group” represented by the above-mentioned R¹include acyl groups represented by the formulas:—(C═O)—R², —(C═O)—OR², —(C═O)—NR²R³, —SO₂—R², —SO—R², —SO₂—NR²R³,—(C═S)—OR² or —(C═S)NR²R³wherein R² and R³ represent (i) a hydrogen atom, (ii) a hydrocarbongroup which may have a substituent or (iii) a heterocyclic group whichmay have a substituent, respectively, or R² and R³ may be linkedtogether with an adjacent nitrogen atom to form a nitrogen-containingcyclic group which may have a substituent.

Among them, preferred are acyl groups represented by the formulas:—(C═O)—R², —(C═O)—NR²R³, —SO₂—R² or —SO₂—NR²R³ [wherein respectivesymbols are as defined above].

Examples of the “hydrocarbon group which may have a substituent” and the“heterocyclic group which may have a substituent” represented by R² orR³ include the same “hydrocarbon group which may have a substituent” and“heterocyclic group which may have a substituent” as those representedby the above-mentioned R¹.

Examples of the “nitrogen-containing cyclic group which may have asubstituent” formed by R² and R³ include 5- to 9-membered (preferably 5-to 7-membered) nitrogen-containing saturated heterocyclic groups whichmay have 1 to 3 hetero atom(s) selected from a nitrogen atom, an oxygenatom and a sulfur atom in addition to carbon atoms and one nitrogenatom. More specific examples include groups represented by the formulas:

Examples of the “substituent” in the “nitrogen-containing cyclic groupwhich may have a substituent” include the same “substituents” in the“homocyclic ring or heterocyclic ring which may have a substituent”represented by the above-mentioned B ring, and the number ofsubstituent(s) is 1 to 5.

Preferable examples of R² and R³ include (i) a hydrogen atom, (ii)optionally halogenated C₁₋₆ alkyl, (iii) C₆₋₁₀ aryl which may have 1 to3 substituent(s), selected from C₁₋₆ alkyl and C₁₋₆ alkoxy, (iii) C₇₋₁₆aralkyl (e.g. benzyl etc.), and (iv) a 5- or 6-membered heterocyclicgroup (e.g. pyridyl, thienyl, furyl etc.).

Preferable examples of the “acyl group” represented by theabove-mentioned R¹ include formyl, optionally halogenated C₁₋₆alkyl-carbonyl (e.g. acetyl, trifluoroacetyl, propionyl etc.), 5- or6-membered heterocyclic carbonyl (e.g. pyridylcarbonyl, thienylcarbonyl,furylcarbonyl etc.), C₆₋₁₄ aryl-carbonyl (e.g. benzoyl, 1-naphthoyl,2-naphthoyl etc.), C₇₋₁₆ aralkyl-carbonyl (e.g. phenylacetyl,3-phenylpropionyl etc.), optionally halogenated C₁₋₆alkylsulfonyl (e.g.methanesulfonyl, trifluoromethanesulfonyl, propylsulfonyl etc.), C₆₋₁₄arylsulfonyl (e.g. benzenesulfonyl, naphthylsulfonyl etc.), carbamoyl,mono-C₁₋₆ alkyl-carbamoyl (e.g. methylcarbamoyl, ethylcarbamoyl etc.),C₁₋₆alkyl-carbamoyl (e.g. dimethylcarbamoyl, diethylcarbamoyl etc.),aminosulfonyl, mono-C₁₋₆ alkylaminosulfonyl (e.g. methylaminosulfonyl,ethylaminosulfonyl etc.), and di-C₁₋₆ alkylaminosulfonyl (e.g.dimethylaminosulfonyl, diethylaminosulfonyl etc.).

Preferable examples of R¹ include hydrogen atom, C₁₋₆ alkyl, C₁₋₆alkyl-carbonyl, carbamoyl, mono-C₁₋₆ alkyl-carbamoyl, di-C₁₋₆alkyl-carbamoyl, aminosulfonyl, mono-C₁₋₆ alkylaminosulfonyl, anddi-C₁₋₆ alkylaminosulfonyl.

Specific examples of the group represented by the above-mentionedformula:

include groups obtained by removing one hydrogen atom from dicycliccondensed benzene rings such as naphthalene ; tetrahydronaphthalene;indane; indene; benzo[a]cycloheptene; benzofuran such as2,3-dihydro-1-benzofuran, 1,3-dihydro-2-benzofuran etc.; chroman;3,4-dihydro-1H-isochromen; benzoxepine such as2,3,4,5-tetrahydro-1-benzoxepine, 1,3,4,5-tetrahydro-2-benzoxepine,1,2,4,5-tetrahydro-3-benzoxepine etc.; benzothiophen such as2,3-dihydro-1-benzothiophen, 1,3-dihydro-2-benzothiophen etc.;thiochroman; 3,4-dihydro-1H-isothiochromen; benzothiepine such as2,3,4,5-tetrahydro-1-benzothiepine, 1,3,4,5-tetrahydro-2-benzothiepine,1,2,4,5-tetrahydro-3-benzothiepine; 3,4-dihydro-2H-1-benzothiopyran;2,3-dihydro-1H-indole; and 1,2,3,4-tetrahydroquinoline;2,3-dihydro-1H-isoindole; 1,2,3,4-tetrahydroisoquinoline; benzazepinesuch as 2,3,4,5-tetrahydro-1H-1-benzazepine,2,3,4,5-tetrahydro-1H-2-benzazepine,2,3,4,5-tetrahydro-1H-3-benzazepine; benzazocine such as1,2,3,4,5,6-hexahydro-1-benzazocine,1,2,3,4,5,6-hexahydro-2-benzazocine,1,2,3,4,5,6-hexahydro-3-benzazocine; benzazonine such as2,3,4,5,6,7-hexahydro-1H-1-benzazonine,2,3,4,5,6,7-hexahydro-1H-2-benzazonine,2,3,4,5,6,7-hexahydro-1H-3-benzazonine, and2,3,4,5,6,7-hexahydro-1H-4-benzazonine; benzoxazole such as2,3-dihydrobenzoxazole; benzothiazole such as 2,3-dihydrobenzothiazole;benzisothiazole such as 2,3-dihydro-1,2-benzisothiazole, and1,3-dihydro-2,1-benzisothiazole; benzimidazole such as2,3-dihydro-1H-benzimidazole; 1,3-dihydro-2,1,3-benzothiadiazole;benzoxazine such as 3,4-dihydro-1H-2,1-benzoxazine,3,4-dihydro-1H-2,3-benzoxazine, 3,4-dihydro-2H-1,2-benzoxazine,3,4-dihydro-2H-1,4-benzoxazine, 3,4-dihydro-2H-1,3-benzoxazine, and3,4-dihydro-2H-3,1-benzoxazine; benzothiazine such as3,4-dihydro-1H-2,1-benzothiazine, 3,4-dihydro-1H-2,3-benzothiazine,3,4-dihydro-2H-1,2-benzothiazine, 3,4-dihydro-2H-1,4-benzothiazine,3,4-dihydro-2H-1,3-benzothiazine, and 3,4-dihydro-2H-3,1-benzothiazine;benzoisothiazine such as 3,4-dihydro-2H-1,2-benzoisothiazine, and3,4-dihydro-1H-2,1-benzoisothiazine;3,4-dihydro-1H-2,13-benzothiadiazine; benzodiazine such as1,2,3,4-tetrahydrocinnoline, 1,2,3,4-tetrahydrophthalazine,1,2,3,4-tetrahydroquinazoline and 1,2,3,4-tetrahydroquinoxaline;benzoxathiine such as 3,4-dihydro-1,2-benzoxathiine,3,4-dihydro-2,1-benzoxathiine, 2,3-dihydro-1,4-benzoxathiine,1,4-dihydro-2,3-benzoxathiine, 4H-1,3-benzoxathiine, and4H-3,1-benzoxathiine; 1,3-benzodioxol; 1,3-benzodithiol; benzodioxinesuch as 3,4-dihydro-1,2-benzodioxine, 2,3-dihydro-1,4-benzodioxine,1,4-dihydro-2,3-benzodioxine, and 4H-1,3-benzodioxine; benzdithiin suchas 3,4-dihydro-1,2-benzdithiine, 2,3-dihydro-1,4-benzdithiine,1,4-dihydro-2,3-benzdithiine, and 4H-1,3-benzdithiine; benzoxazepinesuch as 2,3,4,5-tetrahydro-1,2-benzoxazepine,2,3,4,5-tetrahydro-1,3-benzoxazepine,2,3,4,5-tetrahydro-1,4-benzoxazepine,2,3,4,5-tetrahydro-1,5-benzoxazepine,1,3,4,5-tetrahydro-2,1-benzoxazepine,1,3,4,5-tetrahydro-2,3-benzoxazepine,1,3,4,5-tetrahydro-2,4-benzoxazepine,1,2,4,5-tetrahydro-3,1-benzoxazepine,1,2,4,5-tetrahydro-3,2-benzoxazepine, and1,2,3,5-tetrahydro-4,1-benzoxazepine; benzothiazepine such as2,3,4,5-tetrahydro-1,2-benzothiazepine,2,3,4,5-tetrahydro-1,4-benzothiazepine,2,3,4,5-tetrahydro-1,5-benzothiazepine,1,3,4,5-tetrahydro-2,1-benzothiazepine,1,3,4,5-tetrahydro-2,4-benzothiazepine,1,2,4,5-tetrahydro-3,1-benzothiazepine,1,2,4,5-tetrahydro-3,2-benzothiazepine, and1,2,3,5-tetrahydro-4,1-benzothiazepine; benzodiazepine such as2,3,4,5-tetrahydro-1H-1,2-benzodiazepine,2,3,4,5-tetrahydro-1H-1,3-benzodiazepine,2,3,4,5-tetrahydro-1H-1,4-benzodiazepine,2,3,4,5-tetrahydro-1H-1,5-benzodiazepine,2,3,4,5-tetrahydro-1H-2,3-benzodiazepine, and2,3,4,5-tetrahydro-1H-2,4-benzodiazepine; benzodioxepine such as4,5-dihydro-1,3-benzodioxepine, 4,5-dihydro-3H-1,2-benzodioxepine,2,3-dihydro-5H-1,4-benzodioxepine, 3,4-dihydro-2H-1,5-benzodioxepine,4,5-dihydro-1H-2,3-benzodioxepine, and 1,5-dihydro-2,4-benzodioxepine;benzodithiepine such as 4,5-dihydro-1H-2,3-benzothiepine,1,5-dihydro-2,4-benzodithiepine, 3,4-dihydro-2H-1,5-benzodithiepine, and2,3-dihydro-5H-1,4-benzodithiepine; benzoxazocine such as3,4,5,6-tetrahydro-2H-1,5-benzoxazocine, and3,4,5,6-tetrahydro-2H-1,6-benzoxazocine; benzothiazocine such as3,4,5,6-tetrahydro-2H-1,5-benzothiazocine, and3,4,5,6-tetrahydro-2H-1,6-benzothiazocine; benzodiazocine such as1,2,3,4,5,6-hexahydro-1,6-benzodiazocine; benzoxathiocine such as2,3,4,5-tetrahydro-1,6-benzoxathiocine; benzodioxocine such as2,3,4,5-tetrahydro-1,6-benzodioxocine; benzotrioxepine such as1,3,5-benzotrioxepine, and 5H-1,3,4-benzotrioxepine; benzoxathiazepinesuch as 3,4-dihydro-1H-5,2,1-benzoxathiazepine,3,4-dihydro-2H-5,1,2-benzoxathiazepine,4,5-dihydro-3,1,4-benzoxathiazepine, and4,5-dihydro-3H-1,2,5-benzoxathiazepine; benzoxadiazepine such as2,3,4,5-tetrahydro-1,3,4-benzoxadiazepine; benzthiadiazepine such as2,3,4,5-tetrahydro-1,3,5-benzthiadiazepine; benzotriazepine such as2,3,4,5-tetrahydro-1H-1,2,5-benzotriazepine;4,5-dihydro-1,3,2-benzoxathiepine, 4,5-dihydro-1H-2,3-benzoxathiepine,3,4-dihydro-2H-1,5-benzoxathiepine, 4,5-dihydro-3H-1,2-benzoxathiepine,4,5-dihydro-3H-2,1-benzoxathiepine, 2,3-dihydro-5H-1,4-benzoxathiepine,and 2,3-dihydro-5H-4,1-benzoxathiepine, inter alia, naphthalene,tetrahydronaphthalene, indane, indene,2,3,4,5-tetrahydro-1H-3-benzazepine,2,3,4,5-tetrahydro-1H-2-benzazepine, 2,3-dihydro-1H-indole,2,3,4,5-tetrahydro-1,4-benzoxazepine, 2,3-dihydro-1-benzofuran, chroman,1,3-dihydro-2H-benzimidazole-2-one, and1,3-dihydro-2,1,3-benzothiadiazole.

Preferable Examples of the case where B ring is a heterocyclic ringinclude the groups represented by the formula:

wherein B′ ring represents a 5- to 9-membered nitrogen-containingheterocyclic ring which may have a substituent, B″ ring represents a 5-to 9-membered oxygen-containing heterocyclic ring which may have asubstituent, and the other respective symbols are as defined above.

Examples of the “5- to 9-membered nitrogen-containing heterocyclic ring”in the “5- to 9-membered nitrogen-containing heterocyclic ring which mayhave a substituent” include 5- to 9-membered nitrogen-containingheterocyclic rings which may have 1 to 3 hetero atom(s) selected from anitrogen atom, an oxygen atom and a sulfur atom in addition to carbonatoms and one nitrogen atom, and 5- to 9-membered non-aromaticnitrogen-containing heterocyclic rings (e.g. pyrrolidine, piperidine,hexamethyleneimine, heptamethyleneimine, piperazine, homopiperazine,tetrahydrooxazepine, morpholine, thiomorpholine, hexahydropyrimidine,imidazolidine, thiadiazolidine etc.) are preferably used. Examples ofthe “substituent” include 1 to 3 substituent(s) selected from the samesubstituents as “substituents” in the “homocyclic ring or heterocyclicring which may have a substituent” represented by above-mentioned Bring.

Examples of the “5- to 9-membered oxygen-containing heterocyclic ring”in the “5- to 9-membered oxygen-containing heterocyclic ring which mayhave a substituent” include 5- to 9-membered oxygen-containingheterocyclic rings which may contain 1 to 3 hetero atom(s) selected froman oxygen atom and a sulfur atom in addition to carbon atoms and oneoxygen atom, and 5- to 9-membered non-aromatic oxygen-containingheterocyclic rings (e.g. tetrahydrofuran, tetrahydropyran, oxepane etc.)are preferably used. Examples of the “substituent” include 1 to 3substituent(s) selected from the same substituents as those in the“homocyclic ring or heterocyclic ring which may have a substituent”represented by above-mentioned B ring, and preferred are oxo, C₁₋₆alkyl, C₁₋₆ alkyl-carbonylamino, and C₁₋₆ alkylsulfonylamino.

Among the groups represented by the formula:

more preferable examples include the groups represented by the formulas:

wherein Ba ring represents a homocyclic ring or a heterocyclic ringwhich may have a substituent, R^(1′) is as defined above for R¹, and theother symbols are as defined above.

Examples of the “substituent” in the “homocyclic ring or heterocyclicring which may have a substituent” represented by Ba ring include 1 or 2substituent(s) selected from substituents other than an oxo group among“substituents” in the “homocyclic ring or heterocyclic ring which mayhave a substituent” represented by above-mentioned B ring.

It is preferable that A ring is a benzene ring which may have 1 or 2substituent(s) selected from aminosulfonyl, mono- or di-C₁₋₆alkylaminosulfonyl, carbamoyl and mono- or di-C₁₋₆ alkyl-carbamoyl, Baring may have 1 or 2 substituent(s) selected from C₁₋₆ alkyl, C₁₋₆alkyl-carbonylamino and C₁₋₆ alkylsulfonylamino, and R¹ and R^(1′)represent (1) a C₁₋₆ alkyl group or a C₇₋₁₆ aralkyl group, each of whichmay have 1 or 2 substituent(s) selected from hydroxy and C₁₋₆alkoxy-carbonyl, or (2) formulas: —(C═O)—R^(2′), —(C═O)—NR^(2′)R^(3′) or—SO₂R^(2′) [wherein R^(2′) and R^(3′) represent hydrogen atom,optionally halogenated C₁₋₆ alkyl or C₁₋₆ or C₆₋₁₀ aryl], respectively.

Specific examples of the case where the phenyl group in the “optionallycondensed phenyl group, and said phenyl group may have a substituent” ofthe above-mentioned (b) is condensed with a dicyclic homocyclic ring orheterocyclic ring which may have a substituent, or is condensed with twosame or different monocyclic homocyclic rings or heterocyclic ringsinclude groups represented by the formula:

wherein A ring is as defined above, and C ring and D ring represent ahomocyclic ring or a heterocyclic ring which may have a substituent.

Examples of the “homocyclic ring” in the “homocyclic ring which may havea substituent” represented by C ring or D ring include the samehomocyclic rings as “homocyclic rings” in the “homocyclic ring which mayhave a substituent” represented by B ring.

Examples of the “heterocyclic ring” in the “heterocyclic ring which mayhave a substituent” represented by C ring or D ring include 5- to9-membered heterocyclic rings which may have 1 to 3 hetero atom(s)selected from a nitrogen atom, an oxygen atom and a sulfur atom (e.g.pyridine, pyrazine, pyrimidine, imidazole, furan, thiophen,dihydropyridine, diazepine, oxazepine, pyrrolidine, piperidine,hexamethyleneimine, heptamethyleneimine, tetrahydrofuran, piperazine,homopiperazine, tetrahydrooxazepine, morpholine, thiomorpholine,hexahydropyrimidine, imidazolidine, thiadiazolidine etc.).

Examples of the “substituent” in the “homocyclic ring or heterocyclicring optionally having a substituent” represented by C ring or D ringinclude the same substituents as “substituents” in the “homocyclic ringor heterocyclic ring which may have a substituent” represented byabove-mentioned B ring.

Specific examples of the groups represented by the aforementionedformula:

wherein respective symbols are as defined above, include groups obtainedby removing one hydrogen atom from tricyclic condensed benzene ringssuch as anthracene, carbazole, 1,2,3,4,4a,9a-hexahydrocarbazole,9,10-dihydroacridine, 1,2,3,4-tetrahydroacridine,10,11-dihydro-5H-dibenz[b,f]azepine,5,6,7,12-tetrahydrodibenz[b,g]azocine,6,11-dihydro-5H-dibenz[b,e]azepine, 6,7-dihydro-5H-dibenz[c,e]azepine,5,6,11,12-tetrahydrodibenz[b,f]azocine, dibenzofuran, 9H-xanthene,10,11-dihydrodibenz[b,f]oxepine, 6,11-dihydrodibenz[b,e]oxepine,6,7-dihydro-5H-dibenz[b,g]oxocine, dibenzothiophen, 9H-thioxanthene,10,11-dihydrodibenzo[b,f]thiepine 6,11-dihydrodibenzo[b,e]thiepine,6,7-dihydro-5H-dibenzo[b,g]thiocine, 10H-phenothiazine, 10H-phenoxazine,5,10-dihydrophenazine, 10,11-dibenzo[b,f][1,4]thiazepine,10,11-dihydrodibenz[b,f][1,4]oxazepine,2,3,5,6,11,11a-hexahydro-1H-pyrrolo[2,1-b][3]benzazepine,10,11-dihydro-5H-dibenzo[b,e][1,4]diazepine,5,11-dihydrodibenz[b,e][1,4]oxazepine,5,11-dihydrodibenzo[b,f][1,4]thiazepine,10,11-dihydro-5H-dibenzo[b,e][1,4]diazepine, and 1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole.

Examples of the groups represented by the above-mentioned formula:

wherein respective symbols are as defined above, include groups obtainedby removing one hydrogen atom from tricyclic condensed benzene ringssuch as phenalene,: acenaphthylene, 1H,3H-naphtho[1,8-cd][1,2]oxazine,naphtho[1,8-de]-1,3-oxazine, naphtho[1,8-de]-1,2-oxazine,1,2,2a,3,4,5-hexahydrobenz[cd]indole,2,3,3a,4,5,6-hexahydro-1H-benzo[de]quinoline,4H-pyrrolo[3,2,1-ij]quinoline,1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline,5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline,1H-pyrrolo[3,2,1-ij]quanazoline, 4H-imidazo[4,5,1-ij]quinoline,2,3,7,8-tetrahydro[1,2,6]thiadiazino[4,3,2-hi]indole,1,2,6,7-tetrahydro-3H,5H-pyrido[3,2,1-ij]quinazoline,2,3,8,9-tetrahydro-7H-[1,2,6]thiadiazino[4,3,2-ij]quinoline,5,6-dihydro-1H,4H-[1,2,5]thiadiazolo[4,3,2-ij]quinoline,1H,5H-benzo[ij]quinolizine, azepino[3,2,1-hi]indole,1,2,4,5,6,7-hexahydroazepino[3,2,1-hi]indole,1H-pyrido[3,2,1-jk][1]benzazepine,5,6,7,8-tetrahydro-1H-pyrido[3,2,1-jk][1]benzazepine,1,2,5,6,7,8-hexahydro-1H-pyrido[3,2,1-jk][1]benzazepine,2,3-dihydro-1H-benz[de]isoqiunoline,1,2,3,4,4a,5,6,7-octahydronaphtho[1,8-bc]azepine, and2,3,5,6,7,8-hexahydro-1H-pyrido[3,2,1-jk][1]benzazepine.

Specific examples of the group represented by the above-mentionedformula:

wherein respective symbols are as defined above, include groups obtainedby removing one hydrogen atom from tricyclic condensed benzene ringssuch as anthracene, 1,2,3,5,6,7-hexahydrobenzo[1,2-b:4,5-b′]dipyrrole,and 1,2,3,5,6,7-hexahydrocyclopenta[f]indole.

Specific examples of the group represented by the above-mentionedformula:

wherein respective symbols are as defined above, include groups obtainedby removing one hydrogen atom from tricyclic condensed benzene ringssuch as phenanthrolene, 1,2,3,6,7,8-hexahydrocyclopenta[e]indole, and2,3,4,7,8,9-hexahydro-1H-cyclopenta[f]quinoline.

Among them, groups represented by the formulas:

wherein C′ ring and D′ ring represent a 5- to 9-memberednitrogen-containing heterocyclic ring which may have a substituent,respectively, and other respective symbols are as defined above, arepreferable. Among them, groups represented by the formula:

wherein respective symbols are as defined above, are further preferred.

Examples of the “5- to 9-membered nitrogen-containing heterocyclic ringwhich may have a substituent” represented by C′ ring or D′ ring includethe same “5- to 9-membered nitrogen-containing heterocyclic ring whichmay have a substituent” as those represented by B′ ring. As thesubstituent, an oxo group is preferable.

Inter alia, more preferable examples include groups represented by theformulas:

wherein C″ ring and D″ ring represent a nitrogen-containing heterocyclicring which may have a substituent, and the other symbols are as definedabove.

Examples of the “substituent” in the “nitrogen-containing heterocyclicring which may have a substituent” represented by C″ ring and D″ ringinclude 1 to 2 substituent(s) selected from “substituents” other than anoxo group in the “homocyclic ring or heterocyclic ring which may have asubstituent” represented by B ring.

Herein, it is preferable that A ring is a benzene ring which may have 1or 2 substituent(s) selected from aminosulfonyl₁, mono- or di-C₁₋₆alkylaminosulfonyl, carbamoyl and mono- or di-C₁₋₆ alkyl-carbamoyl, C″ring and D″ ring may have 1 or 2 substituent(s) selected from C₁₋₆alkyl, C₁₋₆ alkyl-carbonylamino and C₁₋₆ alkylsulfonylamino, and R¹ is(1) a C₁₋₆ alkyl group or a C₇₋₁₆ aralkyl group, each of which may have1 or 2 substituent(s) selected from hydroxy and C₁₋₆ alkoxy-carbonyl, or(2) the formulas: —(C═O)—R^(2′), —(C═O)—NR^(2′)R^(3′) or —SO₂R^(2′)[wherein R^(2′) and R^(3′) represent hydrogen atom, optionallyhalogenated C₁₋₆ alkyl or C₆₋₁₀ aryl].

Specific examples of the case where the phenyl group in the “optionallycondensed phenyl group, and said phenyl group may have a substituent” ofthe above-mentioned (c) is condensed with a tricyclic homocyclic ring orheterocyclic ring which may have a substituent include groupsrepresented by the formulas:

wherein A ring is as defined above, and E ring, F ring and G ringrepresent a homocyclic ring or a heterocyclic ring which may have asubstituent].

Examples of the “homocyclic ring or heterocyclic ring which may have asubstituent” represented by E ring, F ring or G ring include the same“homocyclic ring or heterocyclic ring which may have a substituent” asthose represented by C ring or D ring.

Among them, preferable examples include:

-   (i) a group represented by the formula:

-    wherein E′ ring, F′ ring and G′ ring represent a 5- to 9-membered    nitrogen-containing heterocyclic ring which may have a substituent,    - - - represents a single bond or a double bond, and the other    symbols are as defined above,-   (ii) a group obtained by removing one hydrogen atom from rings such    as fluoranthene, acephenanthrylene, aceanthrylene, triphenylene,    pyrene, chrysene, naphthacene, preyadene, benzo[a]anthracene,    indeno[1,2-a]indene, cyclopenta[a]phenanthrene,    pyrido[1′,2′:1,2]imidazo[4,5-b]quinoxaline, 1H-2-oxapyrene, and    spiro[piperidine-4.9′-xanthene], and dihydro, tetrahydro, hexahydro,    octahydro, decahydro compounds thereof.

Examples of the “5- to 9-membered nitrogen-containing heterocyclic ringwhich may have a substituent” represented by E′ ring, F′ ring and G′ring include the same “5- to 9-membered nitrogen-containing heterocyclicrings which may have a substituent” as those represented by B′-ring. Asthe substituent, an oxo group is preferred.

Specific examples o f the group represented by the above-mentionedformula:

wherein respective symbols are as defined above, include groups obtainedby removing one hydrogen atom from tetracyclic condensed benzene ringssuch as 2H-isoindolo[2,1-e]purine,1H-pyrazolo[4′,3′:3,4]pyrido[2,1-a]isoindole,1H-pyrido[2′,3′:4,5]imidazo[2,1-a]isoindole, 2H,6H-pyrido[2′,2′:3,4]imidazo[5,1-a]isoindole,1H-isoindolo[2,1-a]benzimidazole,1H-pyrido[3′,4′:4,5]pyrrolo[2,1-a]isoindole,2H-pyrido[4′,3′:4,5]pyrrolo[2,1-a]isoindole, 1H-isoindolo[2,1-a]indole,2H-isoindolo[1,2-a]isoindole,1H-cyclopenta[4,5]pyrimido[2,1-a]isoindole,2H,4H-pyrano[4′,3′:4,5][1,3]oxazino[2,3-a]isoindole,2H-isoindolo[2,1-a][3,1]benzoxazine,7H-isoindolo[1,2-b][1,3]benzoxazine,2H-pyrido[2′,1′:3,4]pyrazino[2,1-a]isoindole,pyrido[2′,3′:4,5]pyrimido[2,1-a]isoindole,pyrido[3′,2′:5,6]pyrimido[2,1-a]isoindole,1H-pyrido[1′,2′:3,4]pyrimido[2,1-a]isoindole,isoindolo[2,1-a]quinazoline, isoindolo[2,1-a]quinoxaline,isoindolo[1,2-a]isoquinoline, isoindolo[2,1-b]isoquinoline,isoindolo[2,1-a]quinoline,6H-oxazino[3′,4′:3,4][1,4]diazepino[2,1-a]isoindole,azepino[2′,1′:3,4]pyrazino[2,1-a]isoindole,2H,6H-pyrido[2′,1′:3,4][1,4]diazepino[2,1-a]isoindole,1H-isoindolo[1,2-b][1,3,4]benzotriazepine,2H-isoindolo[2,1-a][1,3,4]benzotriazepine,isoindolo[2,1-d][1,4]benzoxazepine,1H-isoindolo[2,1-b][2,4]benzodiazepine,1H-isoindolo[2,1-c][2,3]benzodiazepine,2H-isoindolo[1,2-a][2,4]benzodiazepine,2H-isoindolo[2,1-d][1,4]benzodiazepine, 5H-indolo[2,1-b][3]benzazepine,2H-isoindolo[1,2-a][2]benzazepine, 2H-isoindolo[1,2-b][3]benzazepine,2H-isoindolo[2,1-b][2]benzazepine,2H-isoindolo[1,2-b][1,3,4]benzoxadiazocine,isoindolo[2,1-b][1,2,6]benzotriazocine, and5H-4,8-methano-1H-[1,5]diazacycloundecino[1,11-a]indole.

Specific examples of the group represented by the above-mentionedformula:

wherein respective symbols are as defined above, include groups obtainedby removing one hydrogen atom from tetracyclic condensed benzene ringssuch as 1H,4H-pyrrolo[3′,2′:4,5]pyrrolo[3,2,1-ij]quinoline,pyrrolo[3,2,1-jk]carbazole,1H-furo[2′,3′:4,5]pyrrolo[3,2,1-ij]quinoline,1H,4H-cyclopenta[4,5]pyrrolo[1,2,3-de]quinoxaline,1H,4H-cyclopenta[4,5]pyrrolo[3,2,1-ij]quinoline,pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]benzoxazine,[1,4]oxazino[2,3,4-jk]carbazole, 1H,3H-[1,3]oxazino[5,4,3-jk]carbozole,pyrido[3′,4′:4,5]pyrrolo[1,2,3-de][1,4]benzothiazine,4H-pyrrolo[3,2,1-de]phenanthridine,4H,5H-pyrido[3,2,1-de]phenanthridine, 1H,4H-3a,6a-diazafluoroanthene,1-oxa-4,6a-diazafluoroanthene, 4-oxa-2,10b-diazafluoroanthene,1-thia-4,6a-diazafluoroanthene, 1H-pyrazino[3,2,1-jk]carbazole,1H-indolo[3,2,1-de][1,5]naphthyridine,benzo[b]pyrano[2,3,4-hi]indolizine,1H,3H-benzo[b]pyrano[3,4,5-hi]indolizine,1H,4H-pyrano[2′,3′:4,5]pyrrolo[3,2,1-ij]quinoline,1H,3H-benzo[b]thiopyrano[3,4,5-hi]indolizine,1H-pyrido[3,2,1-jk]carbazole, 4H-3-oxa-11b-azacyclohepta[jk]fluorene,2H-azepino[1′,2′:1,2]pyrimidino[4,5-b]indole,1H,4H-cyclohepta[4,5]pyrrolo[1,2,3-de]quinoxaline,5H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-ef][1,5]benzoxazepine,4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-jk][4,1]benzothiazepine,5H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepine,5H-pyrido[4′,3′:4,5]pyrrolo[1,2,3-ef][1,5]benzothiazepine,[1,2,4]triazepino[6,5,4-jk]carbazole,[1,2,4]triazepino[6,7,1-jk]carbazole,[1,2,5]triazepino[3,4,5-jk]carbazole,5H-[1,4]oxazepino[2,3,4-jk]carbazole,5H-[1,4]thiazepino[2,3,4-jk]carbazole,[1,4]diazepino[3,2,1-jk]carbazole, [1,4]diazepino[6,7,1-jk]carbazole,azepino[3,2,1-jk]carbazole,1H-cycloocta[4,5]pyrrolo[1,2,3-de]quinoxaline, and1H-cycloocta[4,5]pyrrolo[3,2,1-ij]quinoline.

Specific examples of the group represented by the above-mentionedformula:

wherein respective symbols are as defined above, include groups obtainedby removing one hydrogen atom from tetracyclic condensed benzene ringssuch as 1H-indolo[1,2-a]benzimidazole, 1H-indolo[1,2-b]indazole,pyrrolo[2′,1′:3,4]pyrazino[1,2-a]indole,1H,5H-pyrrolo[1′,2′:4,5]pyrazino[1,2-a]indole,2H-pyrido[2′,3′:3,4]pyrrolo[1,2-a]indole,1H-pyrrolo[2′,3′:3,4]pyrido[1,2-a]indole, 1H-indolo[1,2-a]indole,6H-isoindolo[2,1-a]indole, 6H-indolo[1,2-c][1,3]benzoxazine,1H-indolo[1,2-b][1,2]benzothiazine,pyrimido[4′,5′:4,5]pyrimido[1,6-a]indole,pyrazino[2′,3′:3,4]pyrido[1,2-a]indole,6H-pyrido[1′,2′:3,4]pyrimido[1,6-a]indole, indolo[l,2-b]cinnoline,indolo[1,2-a]quinazoline, indolo[1,2-c]quinazoline,indolo[2,1-b]quinazoline, indolo[1,2-a]quinoxaline,indolo[1,2-a][1,8]naphthyridine, indolo[1,2-b]-2,6-naphthyridine,indolo[1,2-b][2,7]naphthyridine, indolo[1,2-h]-1,7-naphthyridine,indolo[1,2-b]isoquinoline, indolo[2,1-a]isoquinoline,indolo[1,2-a]quinoline,2H-6H-pyrido[2′,1′:3,4][1,4]diazepino[1,2-a]indole,1H-indolo[2,1-c][1,4]benzodiazepine,2H-indolo[1,2-d][1,4]benzodiazepine,2H-indolo[2,1-a][2,3]benzodiazepine,2H-indolo[2,1-b][1,3]benzodiazepine, 1H-indolo[1,2-b][2]benzazepine,2H-indolo[1,2-a][1]benzazepine, 2H-indolo[2,1-a][2]benzazepine,indolo[1,2-e][1,5]benzodiazocine, and indolo[2,1-b][3]benzazocine.

Specific examples of the group represented by the above-mentionedformula:

wherein respective symbols are as defined above, include groups obtainedby removing one hydrogen atom from tetracyclic condensed benzene ringssuch as 1H-imidazo[1′,2′:1,2]pyrido[3,4-b]indole,1H-imidazo[1′,2′:1,6]pyrido[4,3-b]indole,1H-imidazo[1′,5′:1,2]pyrido[3,4-b]indole,1H-imidazo[1′,5′:1,6]pyrido[4,3-b]indole,1H-pyrido[2′,1′:2,3]imidazo[4,5-b]indole, imidazo[4,5-a]carbazole,imidazo[4,5-c]carbazole, pyrazolo[3,4-c]carbazole,2H-pyrazino[1′,2′:1,5]pyrrolo[2,3-b]indole,1H-pyrrolo[1′,2′:1,2]pyrimido[4,5-b]indole, 1H-indolizino[6,7-b]indole,1H-indolizino[8,7-b]indole, indolo[2,3-b]indole, indolo[3,2-b]indole,pyrrolo[2,3-a]carbazole, pyrrolo[2,3-b]carbazole,pyrrolo[2,3-c]carbazole, pyrrolo[3,2-a]carbazole,pyrrolo[3,2-b]carbazole, pyrrolo[3,2-c]carbazole,pyrrolo[3,4-a]carbazole, pyrrolo[3,4-b]carbazole,pyrrolo[3,4-c]carbazole, 1H-pyrido[3′,4′:4,5]furo[3,2-b]indole,1H-furo[3,4-a]carbazole, 1H-furo[3,4-b]carbazole,1H-furo[3,4-c]carbazole, 2H-furo[2,3-a]carbazole,2H-furo[2,3-c]carbazole, 2H-furo[3,2-a]carbazole,2H-furo[3,2-c]carbazole, 1H-pyrido[3′,4′:4,5]thieno[2,3-b]indole,thieno[3′,2′:5,6]thiopyrano[4,3-b]indole,thieno[3′,4′:5,6]thiopyrano[4,3-b]indole,1H-[1]benzothieno[2,3-b]indole, 1H-[1]benzothieno[3,2-b]indole,1H-thieno[3,4-a]carbazole, 2H-thieno[2,3-b]carbazole,2H-thieno[3,2-a]carbazole, 2H-thieno[3,2-b]carbazole,cyclopenta[4,5]pyrrolo[2,3-f]quinoxaline,cyclopenta[5,6]pyrido[2,3-b]indole,pyrido[2′,3′:3,4]cyclopenta[1,2-b]indole,pyrido[2′,3′:4,5]cyclopenta[1,2-b]indole,pyrido[3′,4′:3,4]cyclopenta[1,2-b]indole,pyrido[3′,4′:4,5]cyclopenta[1,2-b]indole,pyrido[4′,3′:4,5]cyclopenta[1,2-b]indole,1H-cyclopenta[5,6]pyrano[2,3-b]indole,1H-cyclopenta[5,6]thiopyrano[4,3-b]indole, cyclopenta[a]carbazole,cyclopenta[c]carbazole, indeno[1,2-b]indole, indeno[2,1-b]indole,[1,2,4]triazino[4′,3′:1,2]pyrido[3,4-b]indole,1,3,5-triazino[1′,2′:1,1]pyrido[3,4-b]indole,1H-[1,4]oxazino[4′,3′:1,2]pyrido[3,4-b]indole,1H-[1,4]oxazino[4′,3′:1,6]pyrido[3,4-b]indole,4H-[1,3]oxazino[3′,4′:1,2]pyrido[3,4-b]indole,indolo[3,2-b][1,4]benzoxazine, 1,3-oxazino[6,5-b]carbazole,2H-pyrimido[2′,1′:2,3][1,3]thiazino[5,6-b]indole,2H-[1,3]thiazino[3′,2′:1,2]pyrido[3,4-b]indole,4H-[1,3]thiazino[3′,4′:1,2]pyrido[3,4-b]indole,indolo[2,3-b][1,4]benzothiazine, indolo[3,2-b][1,4]benzothiazine,indolo[3,2-c][2,1]benzothiazine, 1,4-thiazino[2,3-a]carbazole,[1,4]thiazino[2,3-b]carbazole, [1,4]thiazino[2,3-c]carbazole,1,4-thiazino[3,2-b]carbazole, 1,4-thiazino[3,2-c]carbazole,1H-indolo[2,3-g]pteridine, 1H-indolo[3,2-g]pteridine,pyrazino[1′,2′:1,2]pyrido[3,4-b]indole,pyrazino[1′,2′:1,2]pyrido[4,3-b]indole,1H-pyrido[2′,3′:5,6]pyrazino[2,3-b]indole,1H-pyrido[3′,2′:5,6]pyrazino[2,3-b]indole,1H-pyrido[3′,4′:5,6]pyrazino[2,3-b]indole,pyrido[1′,2′:1,2]pyrimido[4,5-b]indole,pyrido[1′,2′:1,2]pyrimido[5,4-b]indole,pyrido[2′,1′:2,3]pyrimido[4,5-b]indole,pyrimido[1′,2′:1,2]pyrido[3,4-b]indole,pyrimido[1′,2′:1,6]pyrido[3,4-b]indole,pyrimido[5′,4′:5,6]pyrano[2,3-b]indole,pyridazino[4′,5′:5,6]thiopyrano[4,5-b]indole, 1H-indolo[3,2-c]cinnoline,1H-indolo[2,3-b]quinoxaline, 1H-pyrazino[2,3-a]carbazole,1H-pyrazino[2,3-b]carbazole, 1H-pyrazino[2,3-c]carbazole,1H-pyridazino[3,4-c]carbazole, 1H-pyridazino[4,5-b]carbazole,1H-pyrimido[4,5-a]carbazole, 1H-pyrimido[4,5-c]carbazole,1H-pyrimido[5,4-a]carbazole, 1H-pyrimido[5,4-b]carbazole,1H-pyrimido[5,4-c]carbazole,7H-1,4-dioxino[2′,3′:5,6][1,2]dioxino[3,4-b]indole,6H-[1,4]benzodioxino[2,3-b]indole, 6H-[1,4]benzodithiino[2,3-b]indole,1H-indolo[2,3-b]-1,5-naphthyridine, 1H-indolo[2,3-b][1,6]naphthyridine,1H-indolo[2,3-b][1,8]naphthyridine, 1H-indolo[2,3-c]-1,5-naphthyridine,1H-indolo[2,3-c][1,6]naphthyridine, 1H-indolo[2,3-c][1,7]naphthyridine,1H-indolo[2,3-c][1,8]naphthyridine, 1H-indolo[3,2-b]-1,5-naphthyridine,1H-indolo[3,2-b][1,7]naphthyridine, 1H-indolo[3,2-b][1,8]naphthyridine,1H-indolo[3,2-c][1,8]naphthyridine, indolo[2,3-a]quinolizine,indolo[2,3-b]quinolizine, indolo[3,2-a]quinolizine,indolo[3,2-b]quinolizine, pyrano[4′,3′:5,6]pyrido[3,4-b]indole,pyrido[4′,3′:4,5]pyrano[3,2-b]indole,pyrido[4′,3′:5,6]pyrano[2,3-b]indole,pyrido[4′,3′:5,6]pyrano[3,4-b]indole, 1H-indolo[2,3-c]isoquinoline,1H-indolo[3,2-c]isoquinoline, 1H-indolo[2,3-c]quinoline,1H-indolo[3,2-c]quinoline, 1H-pyrido[2,3-a]carbazole,1H-pyrido[2,3-b]carbazole, 1H-pyrido[2,3-c]carbazole,1H-pyrido[3,2-a]carbazole, 1H-pyrido[3,2-b]carbazole,1H-pyrido[3,2-c]carbazole, 1H-pyrido[3,4-a]carbazole,1H-pyrido[3,4-b]carbazole, 1H-pyrido[3,4-c]carbazole,1H-pyrido[4,3-a]carbazole, 1H-pyrido[4,3-b]carbazole,1H-pyrido[4,3-c]carbazole, 1H-quindoline, 1H-quininedoline,1H-pyrano[3′,4′:5,6]pyrano[4,3-b]indole, [1]benzopyrano[2,3-b]indole,[1]benzopyrano[3,2-b]indole, [1]benzopyrano[3,4-b]indole,[1]benzopyrano[4,3-b]indole, [2]benzopyrano[4,3-b]indole,pyrano[2,3-a]carbazole, pyrano[2,3-b]carbazole, pyrano[2,3-c]parbazole,pyrano[3,2-a]carbazole, pyrano[3,2-c]carbazole, pyrano[3,4-a]carbazole,1H-phosphinolino[4,3-b]indole, [1]benzothiopyrano[2,3-b]indole,[1]benzothiopyrano[3,2-b]indole, [1]benzothiopyrano[3,4-b]indole,[1]benzothiopyrano[4,3-b]indole, [2]benzothiopyrano[4,3-b]indole,1H-benzo[a]carbazole, 1H-benzo[b]carbazole, 1H-benzo[c]carbazole,[1,6,2]oxathiazepino[2′,3′:1:2]pyrido[3,4-b]indole,1H-azepino[1′,2′:1,2]pyrido[3,4-b]indole,1H-pyrido[1′,2′:1,2]azepino[4,5-b]indole,2H-pyrido[1′,2′:1,2]azepino,[3,4-b]indole,1H-pyrido[3′,2′:5,6]oxepino[3,2-b]indole,1H-pyrido[4′,3′:5,6]oxepino[3,2-b]indole,2H-pyrido[2′,3′:5,6]oxepino[2,3-b]indole,2H-pyrido[2′,3′:5,6]oxepino[3,2-b]indole,2H-pyrido[3′,4′:5,6]oxepino[3,2-b]indole,pyrido[2′,3′:4,5]cyclohepta[1,2-b]indole,pyrido[3′,2′:3,4]cyclohepta[1,2-b]indole,pyrido[3′,4′:4,5]cyclohepta[1,2-b]indole,pyrido[3′,4′:5,6]cyclohepta[1,2-b]indole,2H-pyrano[3′,2′:2,3]azepino[4,5-b]indole,1H-indolo[3,2-b][1,5]benzoxazepine, 1H-indolo[3,2-d][1,2]benzoxazepine,1H-indolo[2,3-c][1,5]benzothiazepine, [1,4]diazepino[2.3-a]carbazole,indolo[2,3-b][1,5]benzodiazepine, indolo[2,3-d][1,3]benzodiazepine,indolo[3,2-b][1,4]benzodiazepine, indolo[3,2-b][1,5]benzodiazepine,indolo[3,2-d][1,3]benzodiazepine, indolo[3,2-d][2,3]benzodiazepine,indolo[2,3-a][3]benzazepine, indolo[2,3-c][1]benzazepine,indolo[2,3-d][1]benzazepine, indolo[2,3-d][2]benzazepine,indolo[3,2-b][1]benzazepine, indolo[3,2-c][1]benzazepine,indolo[3,2-d][1]benzazepine, 1H-indolo[2,1-b][3]benzazepine,1H-[1]benzoxepino[5,4-b]indole, 1H-[2]benzoxepino[4,3-b]indole,1H-[1]benzothiepino[4,5-b]indole, 1H-[1]benzothiepino[5,4-b]indole,benzo[3,4]cyclohepta[1,2-b]indole, benzo[4,5]cyclohepta[1,2-b]indole,benzo[5,6]cyclohepta[1,2-b]indole, benzo[6,7]cyclohepta[1,2-b]indole,cyclohepta[b]carbazole, 4H-[1,5]oxazocino[5′,4′:1,6]pyrido[3,4-b]indole,azocino[1′,2′:1,2]pyrido[3,4-b]indole,2,6-methano-2H-azecino[4,3-b]indole,3,7-methano-3H-azecino[5,4-b]indole,pyrido[1′,2′:1,8]azocino[5,4-b]indole,pyrido[4′,3′:6,7]oxocino[2,3-b]indole,pyrido[4′,3′:6,7]oxocino[4,3-b]indole,1,5-methano-1H-azecino[3,4-b]indole,2,6-methano-1H-azecino[5,4-b]indole,1H-pyrido[3′,4′:5,6]cycloocta[1,2-b]indole,1,4-ethanooxocino[3,4-b]indole, pyrano[3′,4′:5,6]cycloocta[1,2-b]indole.1H-indolo[2,3-c][1,2,5,6]benzotetrazocine,1H-indolo[2,3-c][1,6]benzodiazocine,6,13b-methano-13bH-azecino[5,4-b]indole, oxocino[3,2-a]carbazole,1H-benzo[g]cycloocta[b]indole,6,3-(iminomethano]-2H-1,4-thiazonino[9,8-b]indole,1H,3H-[1,4]oxazonino[4′,3′:1,2]pyrido[3,4-b]indole,2H-3,6-ethanoazonino[5,4-b]indole,2H-3,7-methanoazacycloundecino[5,4-b]indole,1H-6,12b-ethanoazonino[5,4-b]indole, indolo[3,2-e][2]benzazonine,5,9-methanoazacycloundecino[5,4-b]indole,3,6-ethano-3H-azecino[5,4-b]indole,3,7-methano-3H-azacycloundecino[5,4-b]indole,pyrano[4′,3′:8,9]azecino[5,4-b]indole,1H-indolo[2,3-c][1,7]benzodiazecine, 1H-indolo[3,2-e][2]benzazecine,benzo[e]pyrrolo[3,2-b]indole, benzo[e]pyrrolo[3,2-g]indole,benzo[e]pyrrolo[3,2,1-hi]indole, benzo[e]pyrrolo[3,4-b]indole,benzo[g]pyrrolo[3,4-b]indole, 1H-benzo[f]pyrrolo[1,2-a]indole,1H-benzo[g]pyrrolo[1,2-a]indole, 2H-benzo[e]pyrrolo[1,2-a]indole,1H-benzo[f]pyrrolo[2,1-a]isoindole, 1H-benzo[g]pyrrolo[2,1-a]isoindole,2H-benzo[e ]pyrrolo[2,1-a]isoindole, isoindolo[6,7,1-cde]indole,spiro[cyclohexane-1,5′-[5H]pyrrolo[2,1-a]isoindole],isoindolo[7,1,2-hij]quinoline, 7,11-methanoazocino[1,2-a]indole,7,11-methanoazocino[2,1-a]isoindole, dibenz[cd,f]indole,dibenz[cd,g]indole, dibenz[d,f]indole, 1H-dibenz[e,g]indole,1H-dibenz[e,g]isoindole, naphtho[1,2,3-cd]indole, naphtho[1,8-ef]indole,naphtho[1,8-fg]indole, naphtho[3,2,1-cd]indole, 1H-naphtho[1,2-e]indole,1H-naphtho[1,2-f]indole_(,) 1H-naphtho[1,2-g]indole,1H-naphtho[2,1-e]indole, 1H-naphtho[2,3-e]indole,1H-naphtho[1,2-f]isoindole, 1H-naphtho[2,3-e]isoindole,spiro[1H-carbazole-1,1′-cyclohexane],spiro[2H-carbazole-2,1′-cyclohexane],spiro[3H-carbazole-3,1′-cyclohexane],cyclohepta[4,5]pyrrolo[3,2-f]quinoline,cyclohepta[4,5]pyrrolo[3,2-h]quinoline, azepino[4,5-b]benz[e]indole,1H-azepino[1,2-a]benz[f]indole, 1H-azepino[2,1-a]benz[f]isoindole,benzo[e]cyclohepta[b]indole, and benzo[g]cyclohepta[b]indole.

Specific example of the group represented by the above-mentionedformula:

wherein respective symbols are as defined above, include groups obtainedby removing one hydrogen atom from tetracyclic condensed benzene ringssuch as 1H-dipyrrolo[2,3-b:3′,2′,1′-hi]indole,spiro[cyclopentane-1,2′(1′H)-pyrrolo[3,2,1-hi]indole],spiro[imidazolidine-4,1′(2′H)-[4H]pyrrolo[3,2,1-ij]quinoline],pyrido[2,3-b]pyrrolo[3,2,1-hi]indole,pyrido[4,3-b]pyrrolo[3,2,1-hi]indole,benzo[de]pyrrolo[3,2,1-ij]quinoline, 3H-pyrrolo[3,2,1-de]acridine,1H-pyrrolo[3,2,1-de]phenanthrydine,spiro[cyclohexane-1,6′-[6H]pyrrolo[3,2,1-ij]quinoline],4,9-methanopyrrolo[3,2,1–1m][1]benzoazocine,spiro[cycloheptane-1,6′-[6H]pyrrolo[3,2,1-ij]quinoline],1H-pyrano[3,4-d]pyrrolo[3,2,1-jk][1]benzazepine,3H-benzo[b]pyrrolo[3,2,1-jk][4,1]benzoxazepine,7H-indolo[1,7-ab][4,1]benzoxazepine,benzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepine,indolo[1,7-ab][1,4]benzodiazepine, indolo[1,7-ab][1]benzazepine,indolo[7,1-ab][3]benzazepine, 1H-cyclohepta[d][3,2,1-jk][1]benzazepine,spiro[azepino [3,2,1-hi]indole-7(4H), 1′-cycloheptane],4H-5,11-methanopyrrolo[3,2,1-no][1]benzazacycloundecine, andspiro[azepino[3,2,1-hi]indole-7(4H),1′-cyclooctane].

Among them, further preferable is a group represented by the formula:

In addition, when the “aromatic ring group” in the “optionally condensed5- or 6-membered aromatic ring group” represented by Ar is, for example,“an aromatic heterocyclic group”, examples of fusion of the “aromaticheterocyclic group” include:

-   (d) the case where the aromatic heterocyclic group is condensed with    a monocyclic aromatic ring which may have a substituent, and-   (e) the case where the aromatic heterocyclic group is condensed with    a di- to tri-cyclic aromatic ring which may have a substituent, or    condensed with two same or different monocyclic aromatic rings.

Specific examples include 1-, 2- or 3-indolyl; 1-, 2- or 3-isoindolyl;2- or 3-benzofuranyl; 2- or 3-benzothiofuranyl; 1- or 3-benzimidazolyl;2-benzoxazolyl; 2-benzothiazolyl; 1,2-benzisothiazol-3-yl;1,2-benzisoxazol-3-yl, 2-, 3- or 4-quinolyl; 1-, 3- or 4-isoquinolyl; 2-or 3-quinoxalinyl; 1- or 4-phthalazinyl; naphthyridinyl such as1,8-naphthyridin-2-yl, and 1,5-naphthyridin-3-yl; 2- or 4-quinazolinyl;3- or 4-cinnolinyl; 9-acridinyl; 2-, 6- or 8-purinyl; 2-, 4-, 6- or8-pteridinyl.

Preferable examples of Ar include groups represented by the formula:

wherein A′ ring is as defined for A ring, and the other symbols are asdefined above.

Herein, as A ring and A′ ring, a benzene ring which may have 1 to 4substituent(s) selected from (i) halogen (fluoro etc.), (ii) C₁₋₆ alkoxy(methoxy etc.), (iii) halogenoC₁₋₆ alkoxy (trifluoromethoxy) etc.), (iv)amino, (v) (mono or di) C₁₋₆ alkylamino (methylamino, ethylamino,dimethylamino, diethylamino etc), (vi) 1-pyrrolidinyl, (vii) piperidino,(viii) 1-piperazinyl, (ix) N-methyl-1-piperazinyl, (x)N-acetyl-1-piperazinyl (xi) morpholino, (xii) hexamethyleneimino, (xiii)imidazolyl, (xiv) C₁₋₆ alkyl (propyl etc.) which may be substituted withcarboxy optionally esterified with C₁₋₆ alkyl (methyl etc.), (xv) loweralkyl-carbonylamino (acetylamino etc.), (xvi) lower alkylsulfonylamino(methylsulfonylamino etc.), (xvii) aminosulfonyl, (xviii) (mono or di)C₁₋₆ alkylaminosulfonyl, (xix) 5- to 7-membered cyclic amino-sulfonyl((1-pyrrolidinyl)sulfonyl, piperidinosulfonyl, (1-piperazinyl)sulfonyl,morpholinosulfonyl etc.), (xx) carbamoyl, (xxi) (mono or di) C₁₋₆alkylcarbamoyl, (xxi) 5- to 7-membered cyclic amino-carbonyl((1-pyrrolidinyl)carbonyl, piperidinocarbonyl, (1-piperazinyl)carbonyl,morpholinocarbonyl etc.), and (xxii) cyano is preferred. Morepreferably, A ring is a benzene ring which may have 1 or 2substituent(s) selected from aminosulfonyl, mono- or di-C₁₋₆alkylaminosulfonyl, carbamoyl and mono- or di-C₁₋₆ alkyl-carbamoyl, andA′ ring is a benzene ring which has 1 or 2 substituent(s) selected fromaminosulfonyl, mono- or di-C₁₋₆ alkylaminosulfonyl, C₁₋₆alkyl-carbonylamino and C₁₋₆ alkylsulfonylamino, and further may have 1to 4 substituent(s) (e.g. C₁₋₆alkoxy etc.).

In addition, it is preferable that Ba ring, C″ ring and D″ ring may have1 or 2 substituent(s) selected from C₁₋₆ alkyl, C₁₋₆ alkyl-carbonylaminoand C₁₋₆ alkylsulfonylamino, and R¹ and R^(1′)are (1) a hydrogen atom,(2) a C₁₋₆ alkyl group or a C₇₋₁₆ aralkyl group, each of which may have1 or 2 substituent(s) selected from hydroxy and C₁₋₆ alkoxy-carbonyl, or(3) a group represented by the formulas: —(C═O)—R^(2′),—(C═O)—NR^(2′)—R^(3′) or —SO₂R^(2′) [wherein R^(2′) and R^(3′) representhydrogen atom, optionally halogenated C₁₋₆ alkyl or C₆₋₁₀ aryl,respectively], respectively.

The “spacer having a main chain of 1 to 10 of atoms” in the “spacerhaving a main chain of 1 to 10 of atoms which may have a substituent”represented by L means an interval in which 1 to 10 atom(s) of a mainchain are linked. Herein, the “atom number of main chain” is counted sothat atoms of a main chain become minimum. For example, an atom numberof 1,2-cyclopentylene is counted as 2, and an atom number of1,3-cyclopentylene is counted as 3.

Examples of the “spacer having a main chain of 1 to 10 of atoms whichmay have a substituent” include a combination of 1 to 5, preferably 1 to3 divalent group(s) selected from —O—, —S—, —CO—, —SO—, —SO₂—,—NR¹⁰—(R¹⁰ represents hydrogen atom, optionally halogenated C₁₋₁₀ alkyl,optionally halogenated C₁₋₆ alkyl-carbonyl, optionally halogenated C₁₋₆alkylsulfonyl), a divalent C₁₋₁₀ non-cyclic hydrocarbon group which mayhave a substituent, a divalent C₃₋₉ cyclic hydrocarbon group which mayhave a substituent and a divalent heterocyclic group which may have asubstituent.

Examples of the “substituent” in the “spacer having a main chain of 1 to10 of atoms which may have a substituent”, that is, the “substituent” inthe “divalent C₁₋₁₀ non-cyclic hydrocarbon group which may have asubstituent”, the “divalent C₃₋₉ cyclic hydrocarbon group which may havea substituent” and the “divalent heterocyclic group which may have asubstituent” include 1 to 5, preferably 1 to 3 substituent(s) selectedfrom halogen atom (e.g fluorine, chlorine, bromine, iodine etc.), oxo,C₁₋₃ alkylenedioxy (e.g. methylenedioxy, ethylenedioxy etc.), nitro,cyano, optionally halogenated C₁₋₆alkoxy, optionally halogenated C₁₋₆alkylthio, hydroxy, amino, mono- or di-C₁₋₆ alkylamino, formyl, carboxy,carbamoyl, thiocarbamoyl, optionally halogenated C₁₋₆ alkyl-carbonyl,C₁₋₆ alkoxy-carbonyl, mono- or di-C₁₋₆ alkyl-carbamoyl, optionallyhalogenated C₁₋₆ alkylsulfonyl, formylamino, optionally halogenated C₁₋₆alkyl-carboxamide, C₁₋₆ alkoxy-carboxamide, C₁₋₆ alkylsulfonylamino,C₁₋₆, alkyl-carbonyloxy, C₁₋₆ alkoxy-carbonyloxy, mono-, di-C₁₋₆alkyl-carbamoyloxy and phenyl. Among them, halogen atom such asfluorine, oxo, hydroxy, and phenyl are preferred.

Examples of the “divalent C₁₋₁₀ non-cyclic hydrocarbon group” in the“divalent C₁₋₁₀ non-cyclic hydrocarbon group which may have asubstituent” include C₁₋₁₀ alkylene, C₂₋₁₀ alkenylene, and C₂₋₁₀alkynylene.

Examples of the “C₁₋₁₀ alkylene” include —CH₂—, —(CH₂)₂—, —(CH₂)₃,—(CH₂)₄—, —(CH₂)₅—, —(CH₂)₆—, —(CH₂)₇—, —(CH₂)₈—, —(CH₂)₉—, —(CH₂)₁₀—,—(CH₂)₃CH(CH₃)—, —(CH₂)₄CH(CH₃)—, —(CH₃)CHCH₂—, —(CH₃)CH(CH₂)₂—, and—(CH(CH₃))₂—.

Examples of the “C₂₋₁₀ alkenylene” include —CH═CH—, —CH₂—CH═CH—,—C(CH₃)₂—CH═CH—, —CH₂—CH═CH—CH₂—, —CH₂—CH₂—CH═CH—, —CH═CH—CH═CH—, and—CH═CH—CH₂—CH₂—CH₂—.

Examples of the “C₂₋₁₀ alkynylene” include —C≡C—, —CH₂—C≡C—,—CH₂—C≡C—CH₂—CH₂—.

Examples of the “divalent C₃₋₉ cyclic hydrocarbon group” in the“divalent C₃₋₉ cyclic hydrocarbon group which may have a substituent”include C₃₋₉ cycloalkylene, C₃₋₉ cycloalkenylene, and C₆₁₄ arylene(phenylene etc.).

Examples of the “C₃-₉ cycloalkylene” include:

and the like.

The examples of the “C₃₋₉ cycloalkenylene” include:

and the like.

Examples of the “divalent heterocyclic group” in the “divalentheterocyclic group which may have a substituent” include groups obtainedby removing two hydrogen atoms from 4- to 14-membered (preferably 5- to9-membered) aromatic or non-aromatic heterocyclic rings containing 1 to4 hetero atom(s) selected from a nitrogen atom, an oxygen atom and asulfur atom. Examples of such the aromatic or non-aromatic heterocyclicring include the same rings as those exemplified for the “heterocyclicring which may have a substituent” represented by the above-mentioned Bring.

As L, C₁₋₁₀ alkylene which may have a substituent is preferred, interalia, a C₂₋₆ alkylene group which may have 1 to 4 substituent(s)selected from halogen atom, hydroxy, oxo and phenyl (e.g. —(CH₂)₂—,—(CH₂)₃—, —(CH₂)₄—, —(CH₂)₅—, —(CH₂)₆—, —CHFCH₂—, —CHF(CH₂)₂—,—CHF(CH₂)₃—, —CHF(CH₂)₄—, —CF₂CH₂—, —CF₂(CH₂)₂—, —CF₂(CH₂)₃—,—CF₂(CH₂)₄—(CH₂)₃CH(CH₃)—, —(CH₂)₄CH(CH₃)—, —(CH₂)₃CH(CF₃)—,—(CH₂)₄CH(CF₃)—, —(CH₃)CHCH₂—, —(CH₃)CH(CH₂)₂—, —(CH(CH₃)₂—,—CH₂CH(OH)—, —CH₂CO—, -(Ph)CHCH₂— etc.) is preferable and, further, C₃₋₇cycloalkylene or a combination of C₃₋₇ cycloalkylene and C₁₋₄ alkylene(e.g.

is also preferable.

Examples of the ring formed between L and Ar include 1-oxoindan-2-yl,1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl,5-oxo-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-6-yl,2,5-dioxo-1,2,3,5,6,7-hexahydroindeno[5,6-d]imidazol-6-yl,2,5-dioxo-2,3,5,6,7,8-hexahydro-1H-naphtho[2,3-d]imidazol-6-yl,2,5-dioxo-1, 2,3,5,6,7,8,9-octahydrocyclohepta[f]benzimidazol-6-yl,2,8-dioxo-2,3,4,6,7,8-hexahydro-1H-cyclopenta[g]quinazolin-7-yl,2,9-dioxo-1,2,3,4,6,7,8,9-octahydrobenzo[g]quinazolin-8-yl,2,10-dioxo-2,3,4,6,7,8,9,10-octahydro-1H-cyclohepta[g]qunazolin-9-yl,2,2-dioxido-5-oxo-3,5,6,7-tetrahydro-1H-indeno[5,6-c][1,2,5]thiadiazol-6-yl,2,2-dioxido-5-oxo-1,3,5,6,7,8-hexahydronaphto[2,3-c][1,2,5]thiadiazol-6-yl,2,2-dioxido-5-oxo-3,5,6,7,8,9-hexahydro-1H-cyclohepta[f][2,1,3]benzothiadiazol-6-yl,2,2-dioxido-8-oxo-1,3,4,6,7,8-hexahydroindeno[5,6-c][1,2,6]thiadiazin-7-yl,2,2-dioxide-9-oxo-3,4,6,7,8,9-hexahydro-1H-naphtho[2,3-c][1,2,6]thiadiazin-8-yl,and2,2-dioxide-10-oxo-1,3,4,6,7,8,9,10-octahydrocyclohepta[g][2,1,3]benzothiadiazin-9-yl.Preferable example includes a ring represented by the formula:

wherein symbols are as defined above.

Examples of the “amino group which may have a substituent” representedby Y include a group represented by the formula:

is wherein R represents a hydrogen atom or a hydrocarbon group which mayhave a substituent, L_(2a) represents a C₁₋₄ alkylene group which mayhave a substituent, X represents a bond, an oxygen atom or a nitrogenatom, and Ar₂ represents an aromatic ring group which may have asubstituent, or Ar₂ and R, or Ar₂ and L_(2a) may be linked together toform a ring.

Examples of the “hydrocarbon group which may have a substituent”represented by R include the same groups as “hydrocarbon groups whichmay have a substituent” represented by R¹.

Examples of the “substituent” in the “hydrocarbon group which may have asubstituent” represented by R include the same groups as “substituents”in the “hydrocarbon group which may have a substituent” represented byR¹, and the number of substituents(s) is 1 to 3.

Examples of the “C₁₋₄ alkylene group which may have a substituent”represented by L_(2a) include groups having the number of carbon chainsof 1 to 4 among “C₁₋₁₀ alkylene groups” exemplified for the “spacerhaving a main chain of 1 to 10 atoms which may have a substituent”represented by L.

Examples of the “substituent” in the “C₁₋₄ alkylene group which may havea substituent” represented by L_(2a) include the same groups as“substituents” in the “spacer having a main chain of 1 to 10 atoms whichmay have a substituent” represented by L.

Examples of the “hydrocarbon group which may have a substituent”, the“acyl group” and the “heterocyclic group which may have a substituent”represented by R^(1a) in the “a bond, an oxygen atom or NR^(1a) (R^(1a)represents a hydrogen atom, a hydrocarbon group which may have asubstituent, an acyl group or a heterocyclic group which may have asubstituent)” represented by X include the same groups as those in R¹.

Examples of the “aromatic ring group” in the “aromatic ring group whichmay have a substituent” represented by Ar₂ include the same groups as“optionally condensed 5- or 6-membered aromatic ring groups” representedby Ar. Examples of the “substituent” in the “aromatic ring group whichmay have a substituent” represented by Ar₂ include the same groups as“substituents” in the “represents an optionally condensed 5- or6-membered aromatic ring group, and said aromatic ring group may have asubstituent” represented by Ar, and the number of substituent(s) is 1 to5.

Examples of the ring formed by binding Ar₂ and R together include ringsrepresented by the formula:

wherein p and q represent an integer of 1 to 3, respectively, and H ringrepresents a benzene ring which may have 1 to 3 substituent(s) selectedfrom halogen, hydroxy, optionally halogenated C₁₋₆ alkyl and optionallyhalogenated C₁₋₆ alkoxy.

Examples of the ring formed by binding Ar₂ and L_(2a) include ringsrepresented by the formula:

wherein r represents an integer of 0 to 2, s represents an integer of 1to 3, and r+s is an integer of 2 to 5, and H ring is as defined above.

Examples of the “nitrogen-containing saturated heterocyclic group” inthe “nitrogen-containing saturated heterocyclic group which may have asubstituent” represented by Y include 5- to 9-membered (preferably 5- to7-membered) nitrogen-containing saturated heterocyclic groups which maycontain 1 to 3 hetero atom(s) selected from a nitrogen atom, an oxygenatom and a sulfur atom in addition to carbon atoms and one nitrogenatom. Specific examples include groups represented by the formulas:

Among them, preferred is a 6-membered cyclic group.

Further preferable is a group represented by the formula:

Examples of the “substituent” in the “nitrogen-saturated heterocyclicgroup which may have a substituent” include the same groups as“substituents” in the “heterocyclic ring which may have a substituent”represented by above-mentioned B ring, and the number of substituent(s)is 1 to 5. In addition, nitrogen in the “nitrogen-containing saturatedheterocyclic group” of the “nitrogen-containing saturated heterocyclicgroup which may have a substituent” may have the same group as a grouprepresented by the formula:

wherein respective symbols are as defined above.

Preferable examples of Y include groups represented by the formulas:

wherein respective symbols are as defined above.

As R, (i) a hydrogen atom, (ii) a C₁₋₄ alkyl group which may have 1 to 3substituent(s) selected from halogen atom (preferably fluoro etc.) andhydroxy, or (iii) a C₇₋₁₆ aralkyl (benzyl etc.) is preferable, and ahydrogen atom or a C₁₋₄ alkyl group is more preferable.

As L_(2a), a C₂₋₄ alkylene group which may have 1 to 4 substituent(s)selected from halogen atom, hydroxy, oxo and phenyl (e.g. —(CH₂)₂—,—(CH₂)₃—, —(CH₂)₄—, —CHFCH₂—, —CHF(CH₂)₂—, —CHF(CH₂)₃, —CF₂CH₂—,—CF₂(CH₂)₂—, —CF₂(CH₂)₃—, —(CH₃)CHCH₂—, —(CH₃)CH(CH₂)₂—, —(CH(CH₃))₂—,—CH₂CH(OH)—, —CH₂CO—, -(Ph)CHCH₂— etc.) is preferable, a C₂₋₃ alkylenegroup which may have hydroxy, oxo or phenyl (e.g. —(CH₂)₂—, —(CH₂)₃—,—(CH₃)CHCH₂—, -(Ph)CHCH₂—, —CH₂CH(OH)—, —CH₂CO— etc.) is morepreferable, and an ethylene group is most preferable.

As X, a bond, an oxygen atom or NH is preferable, and a bond is morepreferable.

Preferable examples of Ar₂ include:

-   (1) (i) a C₆₋₁₀ aryl group (phenyl etc.) or (ii) a 5- or 6-membered    aromatic heterocyclic group containing 1 to 4 hetero atom(s)    selected from a nitrogen atom, an oxygen atom and a sulfur atom    (optionally condensed with a benzene ring) (e.g. thienyl, furyl,    pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl,    isooxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,    oxadiazolyl, thiadiazolyl, furazanyl, indolyl, isoindolyl,    benzofuranyl, quinolyl, isoquinolyl, naphthyridinyl, quinazolinyl,    cinnolinyl, acridinyl etc.), each of which may have 1 to 5    (preferably 1 to 3) substituent(s) selected from halogen (fluoro,    chloro etc.), C₁₋₆ alkyl (methyl, ethyl etc.), halogenoC₁₋₆ alkyl    (trifluoromethyl etc.), hydroxy, C₁₋₆ alkoxy (methoxy, ethoxy etc.),    halogenoC₁₋₆ alkoxy (trifluoromethoxy, trifluoroethoxy etc.), nitro,    amino, cyano, carbamoyl, each of which is optionally substituted    with C₁₋₆ alkyl, amino which may be substituted with carbamoyl or    formyl (NHCHO, NHCONH₂, NHCONHMe etc.), C₁₋₃ alkylenedioxy    (methylenedioxy etc.), aminocarbonyloxy group which may be    substituted with C₁₋₆ alkyl (aminocarbonyloxy,    methylaminocarbonyloxy, ethylaminocarbonyloxy,    dimethylaminocarbonyloxy, diethylaminocarbonyloxy etc.), 5- to    7-membered cyclic amino-carbonyloxy ((1-pyrrolidinyl)carbonyloxy,    piperidinocarbonyloxy etc.), aminosulfonyl, mono-C₁₋₆    alkylaminosulfonyl and di-C₁₋₆ alkylaminosulfonyl,-   (2) the case where Ar₂ and R are linked together to form a ring    represented by the formula:

-    wherein symbols are defined above, or-   (3) the case where Ar₂ and L₂ are linked together to form a ring    represented by the formula:

-    wherein symbols are as defined above.

More preferable examples of Ar₂ include (i) a C₆₋₁₀ aryl group (phenyletc.) or (ii) a 5- or 6-membered aromatic heterocyclic group (optionallycondensed with a benzene ring) containing 1 to 4 hetero atom(s) selectedfrom a nitrogen atom, an oxygen atom and a sulfur atom (tienyl, indolyletc.), each of which may have 1 to 3 substituent(s) selected fromhalogen, nitro, hydroxy, optionally halogenated C₁₋₆ alkyl, optionallyhalogenated C₁₋₆ alkoxy and aminosulfonyl.

More preferable Y is a group represented by the formula:

wherein respective symbols are as defined above.

Preferable Compound (I) is a compound wherein Ar is a group representedby the formulas:

wherein symbols are as defined above, (A ring is preferably a benzenering which may have 1 or 2 substituent(s) selected from aminosulfonyl,mono- or di-C₁₋₆ alkylaminosulfonyl, carbamoyl and mono- or di-C₁₋₆alkyl-carbamoyl, A′ ring is preferably a benzene ring which has 1 or 2substituent(s) selected from aminosulfonyl, mono-or di-C₁₋₆alkylaminosulfonyl, C₁₋₆ alkyl-carbonylamino and C₁₋₆alkylsulfonylamino, and further may have 1 to 4 substituent(s) (e.g.C₁₋₆ alkoxy etc.), Ba ring, C″ ring and D″ ring may preferably have 1 or2 substituent(s) selected from C₁₋₆ alkyl, C₁₋₆ alkyl-carbonylamino andC₁₋₆ alkylsulfonylamino, respectively, and R¹ and R^(1′) preferably are(1) a hydrogen atom, (2) a C₁₋₆ alkyl group or a C₇₋₁₆ aralkyl group(benzyl etc.), each of which may have 1 or 2 substituent(s) selectedfrom hydroxy and C₁₋₆ alkoxy-carbonyl, or (3) a group represented by theformula: —(C═O) —R^(2′), —(C═O) —NR^(2′) R^(3′) or —SO₂R^(2′) [whereinR^(2′) and R^(3′) represent a hydrogen atom, optionally halogenated C₁₋₆alkyl or C₆₋₁₀ aryl, respectively], respectively);

L is (1) a C₂₋₆ alkylene group which may have 1 to 4 substituent(s)selected from halogen atom, hydroxy, oxo and phenyl (e.g. —(CH₂)₂—,—(CH₂)₃—, —(CH₂)₄—, —(CH₂)₅—, —(CH₂)₆—, —CHFCH₂—, —CHF(CH₂)₂—,—CHF(CH₂)₃—, —CHF(CH₂)₄—, —CF₂CH₂—, —CF₂(CH₂)₂—, —CF₂(CH₂)₃—,—CF₂(CH₂)₄—, —(CH₂)₃CH(CH₃)—, —(CH₂)₄CH(CH₃)—, —(CH₂)₃CH (CF₃)—,—(CH₂)₄CH(CH₃)—, —(CH₂)₃CH(CF₃)—, —(CH₂)₄CH(CF₃)—, —(CH₃)CHCH₂—,—(CH₃)CH(CH₂)₂—, —(CH(CH₃))₂—, —CH₂CH(OH)—, —CH₂CO—, -(Ph)CHCH₂— etc.),or (2) C₃₋₇ cycloalkylene or a combination of C₃₋₇ cycloalkylene andC₁₋₄ alkylene (e.g.

Y is a group represented by the formulas:

wherein respective symbols are as defined above,

R is (i) a hydrogen atom, (ii) a C₁₋₄ alkyl group which may have 1 to 3substituent(s) selected from a halogen atom (e.g. fluoro etc.) andhydroxy, or (iii) C₇₋₁₆ aralkyl (benzyl etc.);

L_(2a) is a C₂₋₄ alkylene group which may have 1 to 4 substituent(s)selected from halogen atom, hydroxy, oxo and phenyl (e.g. —(CH₂)₂—,—(CH₂)₃—, —(CH₂)₄—, —CHFCH₂—, —CHF(CH₂)₂—, —CHF(CH₂)₃—, —CF₂CH₂—,—CF₂(CH₂)₂—, —CF₂(CH₂)₃—, —(CH₃)CHCH₂—, —(CH₃)CH(CH₂)₂—, —(CH(CH₃))₂—,—CH₂CH(OH)—, —CH₂CO—, -(Ph)CHCH₂— etc.);

X is a bond, an oxygen atom or NH;

Ar₂ is (1) (i) a C₆₋₁₀ aryl group (phenyl etc.) or (ii) a 5- or6-membered aromatic heterocyclic group (optionally condensed with abenzene ring) containing 1 to 4 hetero atom(s) selected from a nitrogenatom, an oxygen atom and a sulfur atom (e.g. thienyl, furyl, pyrrolyl,imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isooxazolyl,pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxadiazolyl, thiadiazolyl,furazanyl, indolyl, isoindolyl, benzofuranyl, quinolyl, isoquinolyl,naphthyridinyl, quinazolinyl, cinnolinyl, acridinyl etc.), each of whichmay have 1 to 5 (preferably 1 to 3) substituent(s) selected from halogen(fluoro, chloro etc.), C₁₋₆ alkyl (methyl, ethyl etc.), halogenoC₁₋₆alkyl (trifluoromethyl etc.), hydroxy, C₁₋₆ alkoxy (methoxy, ethoxyetc.), halogenoC₁₋₆ alkoxy (trifluoromethoxy, trifluoroethoxy etc.),nitro, amino, cyano, carbamoyl, carbamoyl which may be substituted withC₁₋₆ alkyl or amino which may be substituted with formyl (NHCHO,NHCONH₂, NHCONHMe etc.), C₁₋₃ alkylenedioxy (methylenedioxy etc.), anaminocarbonyloxy group which may be substituted with C₁₋₆ alkyl(aminocarbonyloxy, methylaminocarbonyloxy, ethylaminocarbonyloxy,dimethylaminocarbonyloxy, diethylaminocarbonyloxy etc.), 5- to7-membered cyclic amino-carbonyloxy ((1-pyrrolidinyl)carbonyloxy,piperidinocarbonyloxy etc.), aminosulfonyl, mono-C₁₋₆ alkylaminosulfonyland di-C₁₋₆ alkylaminosulfonyl, (2) the case where Ar₂ and R are linkedtogether to form a ring represented by the formula:

wherein symbols are as defined above, or (3) the case where Ar₂ and L₂are linked together to form a ring represented by the formula:

wherein symbols are as defined above.

In addition, among Compound(I), a compound represented by the formula:

wherein Ar₁ represents a dicyclic to tetracyclic condensed benzene ringgroup which may have a substituent, L₁ represents a C₄₋₆ alkylene groupwhich may have a substituent, and the other respective symbols are asdefined above, (hereinafter, abbreviated as Compound (Ia) in some cases)or a salt thereof is a novel compound.

The “dicyclic to tetracyclic condensed benzene ring group” in the“dicyclic to tetracyclic condensed benzene ring which may have asubstituent” represented by Ar₁ include the same groups as thoseexemplified with respect to the condensed benzene ring group exemplifiedas an example of condensation of the “phenyl group” in the case that the“5- or 6-membered aromatic ring group” in the “optionally condensed 5-or 6-membered aromatic ring group” represented by Ar is “phenyl group”.

The “substituent” in the “dicyclic to tetracyclic condensed benzene ringgroup which may have a substituent” represented by Ar₁ include the samegroups as those exemplified with respect to the “substituent” in the“represents optionally condensed 5- or 6-membered aromatic ring group,and said aromatic ring group may have a substituent” represented by Ar.

Preferable examples of Ar₁ include groups represented by the formulas:

wherein respective symbols are as defined above.

More preferable examples of Ar₁ include groups represented by theformulas:

wherein respective symbols are as defined above.

Herein, as A ring, a benzene ring which may have 1 to 2 substituent(s)selected from (i) halogen (fluoro etc.), (ii) C₁₋₆ alkoxy(methoxy etc.),(iii) halogenoC₁₋₆ alkoxy (trifluoromethoxy etc.), (iv) amino, (v) (monoor di)C₁₋₆ alkylamino (methylamino, ethylamino, dimethylamino,diethylamino etc.), (vi) 1-pyrrolidinyl, (vii) piperidino, (viii)1-piperazinyl, (ix) N-methyl-1-piperazinyl, (x) N-acetyl-1-piperadinyl,(xi) morpholino, (xii) hexamethyleneimino, (xiii) imidazolyl, (xiv) C₁₋₆alkyl (propyl etc.) which may be substituted with carboxy optionallyesterified with C₁₋₆ alkyl (methyl etc.), (xv) lower alkyl-carbonylamino(acetylamino etc.), (xvi) lower alkylsulfonylamino (methylsulfonylaminoetc.), (xvii) aminosulfonyl, (xviii) (mono or di) C₁₋₆alkylaminosulfonyl, (xix) 5- to 7-membered cyclic amino-sulfonyl((1-pyrrolidinyl)sulfonyl, piperidinosulfonyl, (1-piperazinyl)sulfonyl,morpholinosulfonyl etc.), (xx) carbamoyl, (xxi) (mono or di) C₁₋₆alkylcarbamoyl, (xxi) 5- to 7-membered cyclic amino-carbonyl((1-pyrrolidinyl)carbonyl, piperidinocarbonyl, (1-piperazinyl)carbonyl,morpholinocarbonyl etc.) and (xxii) cyano is preferred. More preferably,A ring is a benzene ring which may have 1 or 2 substituent(s) selectedfrom aminosulfonyl, mono- or di-C₁₋₆ alkylaminosulfonyl, carbamoyl andmono- or di-C₁₋₆ alkyl-carbamoyl.

In addition, it is preferable that Ba ring, C″ ring and D″ ring may have1 or 2 substituent(s) selected from C₁₋₆ alkyl, C₁₋₆ alkyl-carbonylaminoand C₁₋₆ alkylsulfonylamino, respectively, and R¹ and R¹′ are (1) ahydrogen atom, (2) a C₁₋₆ alkyl group or a C₇₋₁₆ aralkyl group, each ofwhich may have 1 or 2 substituent(s) selected from hydroxy and C₁₋₆alkoxy-carbonyl, or (3) a group represented by the formula:—(C═O)—R^(2′), —(C═O)—NR^(2′) R^(3′) or —SO₂R^(2′) [wherein R^(2′) andR^(3′) represent a hydrogen atom, optionally halogenated C₁₋₆ alkyl orC₆₋₁₀ aryl, respectively].

Examples of the “C₄₋₆ alkylene group which may have a substituent”represented by L₁ include those having carbon chain number of 4 to 6among the “C₁₋₁₀ alkylene group” exemplified with respect to the “spacerhaving a main chain of 1 to 10 atoms which may have a substituent”represented by L.

The “substituent” in the “C₄₋₆ alkylene group which may have asubstituent” represented by L₁ include the same groups as thoseexemplified with respect to the “substituent” in the “spacer having amain chain of 1 to 10 atoms which may have a substituent” represented byL. Preferable examples include 1 to 4 substituent(s) selected fromhalogen atom (e.g. fluorine, chlorine, bromine, iodine etc.), nitro,cyano, optionally halogenated C₁₋₆ alkoxy, and hydroxy.

Preferable examples of L₁ include —(CH₂)₄—, —(CH₂)₅—, —(CH₂)₆—,—CHF(CH₂)₃—, —CHF(CH₂)₄—, —CF₂(CH₂)₃—, —CF₂(CH₂)₄—, —(CH₂)₃CH(CH₃)—,—(CH₂)₄CH(CH₃)—, —(CH₂)₃CH(CF₃)—, and —(CH₂)₄CH(CF₃)—.

Compound (Ia) is preferably a compound wherein Ar₁ is a grouprepresented by the formulas:

wherein symbols are as defined above, (more preferably a grouprepresented by:

wherein symbols are as defined above) (A ring is preferably a benzenering which may have 1 or 2 substituent(s) selected from aminosulfonyl,mono- or di-C₁₋₆ alkylaminosulfonyl, carbamoyl and mono- or di-C₁₋₆alkyl-carbamoyl, Ba ring, C″ ring and D″ ring may preferably have 1 or 2substituent(s) selected from C₁₋₆ alkyl, C₁₋₆ alkyl-carbonylamino andC₁₋₆ alkylsulfonylamino, respectively, and R¹ and R^(1′) are preferably(1) a hydrogen atom, (2) a C₁₋₆ alkyl group or a C₇₋₁₆ aralkyl group(benzyl etc.), each of which may have 1 or 2 substituent(s) selectedfrom hydroxy and C₁₋₆ alkoxy-carbonyl, or (3) a group represented by theformula: —(C═O)—R^(2′), —(C═O)—NR^(2′)R^(3′) or —SO₂R^(2′) [whereinR^(2′) and R^(3′) represent hydrogen atom, optionally halogenated C₁₋₆alkyl or C₆₋₁₀ aryl, respectively], respectively);

L₁ is a C₄₋₅ alkylene group which may have 1 or 2 halogen atom(s) suchas —(CH₂)₄—, —(CH₂)₅—, —CHF(CH₂)₃—, —CHF(CH₂)₄—, —CF₂(CH₂)₃—,—CF₂(CH₂)₄—, —CH₂)₃CH(CH₃)—, and —(CH₂)₄CH(CH₃)— (preferablyunsubstituted C₄₋₅ alkylene group);

R is (i) a hydrogen atom, (ii) a C₁₋₄ alkyl group which may have 1 to 3substituent(s) selected from halogen atom (preferably fluoro etc.) andhydroxy, or (iii) C₇₋₁₆ aralkyl (benzyl etc.) (more preferably, hydrogenatom or C₁₋₄ alkyl group);

L₂ is a C₂₋₄ alkylene group which may have 1 to 4 substituent(s)selected from halogen atom, hydroxy, oxo and phenyl (e.g. —(CH₂)₂—,—(CH₂)₃—, —(CH₂)₄—, —CHFCH₂—, CHF(CH₂)₂—, —CHF(CH₂)₃—, —CF₂CH₂—,—CF₂(CH₂)₂—, —CF₂(CH₂)₃—, —(CH₃)CHCH₂—, —(CH₃)CH(CH₂)₂—, —(CH(CH₃))₂—,—CH₂CH(OH)—, —CH₂CO—, -(Ph)CHCH₂— etc.) (more preferably, C₂₋₃ alkylenegroup which may have hydroxy, oxo or phenyl);

X is a bond, an oxygen atom or NH (more preferably, a bond);

Ar₂ is (1) (i) a C₆₋₁₀ aryl group (phenyl etc.) or (ii) a 5- or6-membered aromatic heterocyclic group (optionally condensed with abenzene ring) containing 1 to 4 hetero atom(s) selected from a nitrogenatom, an oxygen atom and a sulfur atom (e.g. thienyl, furyl, pyrrolyl,imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isooxazolyl,pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxadiazolyl, thiadiazolyl,furazanyl, indolyl, isoindolyl, benzofuranyl, quinolyl, isoquinolyl,naphthrydinyl, quinazolinyl, cinnolinyl, acridinyl etc.), each of whichmay have 1 to 5 (preferably 1 to 3) substituents selected from halogen(fluoro, chloro etc.), C₁₋₆ alkyl (methyl, ethyl etc.), halogenoC₁₋₆alkyl (trifluoromethyl etc.), hydroxy, C₁₋₆ alkoxy (methoxy, ethoxyetc.), halogenoC₁₋₆ alkoxy (trifluoromethoxy, trifuloroethoxy etc.),nitro, amino, cyano, carbamoyl, carbamoyl which may be substituted withC₁₋₆ alkyl or amino which may be substituted with formyl (NHCHO,NHCONH₂, NHCONHMe etc.), C₁₋₃ alkylenedioxy (methylenedioxy etc.), anaminocarbonyloxy group which may be substituted with C₁₋₆ alkyl(aminocarbonyloxy, methylaminocarbonyloxy, ethylaminocarbonyloxy,dimethylaminocarbonyloxy, dimethylaminocarbonyloxy etc.), 5- to7-membered cyclic amino-carbonyloxy ((1-pyrrolidinyl)carbonyloxy,piperidinocarbonyloxy etc.), aminosulfonyl, mono-C₁₋₆ alkylaminosulfonyland di-C₁₋₆ alkylaminosulfonyl, (2) the case where Ar₂ and R are linkedtogether to form a ring represented by the formula:

wherein symbols are as defined above, or (3) the case where Ar₂ and L₂are linked together to form a ring represented by the formula:

wherein symbols are as defined above (Ar₂ is more preferably (i) a C₆₋₁₀aryl group (phenyl etc.) or (ii) a 5- or 6-membered aromaticheterocyclic group (optionally condensed with a benzene ring) containing1 to 4 hetero atom(s) selected from a nitrogen atom, an oxygen atom anda sulfur atom (thienyl, indolyl etc.), each of which may have 1 to 3substituent(s) selected from halogen, nitro, hydroxy, optionallyhalogenated C₁₋₆ alkyl, optionally halogenated C₁₋₆ alkoxy andaminosulfonyl).

In addition, among Compound (I), a compound represented by the formula:

wherein Ar₃ represents a benzimidazole ring group, a quinazoline ringgroup, a 1,4-benzoxazine ring group or a tricyclic to tetracycliccondensed benzene ring group, each of which may have a substituent, L₃represents a C₂₋₄ alkylene group which may have a substituent, and theother respective symbols are as defined above (hereinafter, abbreviatedas Compound (Ib) in some cases) or a salt thereof is a novel compound.

The “tricyclic to tetracyclic condensed benzene ring group” in the“tricyclic to tetracyclic condensed benzene ring group which may have asubstituent” represented by Ar₃ include the same groups as thoseexemplified with respect to the condensed benzene ring group exemplifiedas an example of fusing of the “phenyl group” in the case that the “5-or 6-membered aromatic ring group” in the “optionally condensed 5- or6-membered aromatic ring group” represented by Ar is the “phenyl group”.

The “substituent” in the “a benzimidazole ring group, a quinazoline ringgroup, a 1,4-benzoxazine ring group or a tricyclic to tetracycliccondensed benzene ring group, each of which may have a substituent”represented by Ar₃ include the same groups as those exemplified withrespect to the “substituent” in the “represents an optionally condensed5- or 6-membered aromatic ring group, and said aromatic ring group mayhave a substituent” represented by Ar.

Examples of the “C₂₋₄ alkylene group which may have a substituent”represented by L₃ include those having carbon chain number of 2 to 4among the “C₁₋₁₀ alkylene group” exemplified with respect to the “spacerhaving a main chain of 1 to 10 atoms which may have a substituent”represented by L.

The “substituent” in the “C₂₋₄ alkylene group which may have asubstituent” represented by L₃ include the same groups as thoseexemplified with respect to the “substituent” in the “spacer having amain chain of 1 to 10 atoms which may have a substituent” represented byL. Preferable examples include 1 to 4 substituent(s) selected fromhalogen atom (e.g. fluorine, chlorine, bromine, iodine etc.), nitro,cyano, optionally halogenated C₁₋₆ alkoxy, and hydroxy.

Preferable examples of L₃ include a C₂₋₄ alkylene group which may have 1or 2 halogen atom(s), such as —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, —CHFCH₂—,—CHF(CH₂)₂—, —CF₂CH₂—, and —CF₂(CH₂)₂—.

Compound (Ib) is preferably a compound wherein Ar₃ is a grouprepresented by the formulas:

wherein respective symbols are as defined above (among the groups, it ispreferable that A ring is unsubstituted, and C′ ring and D′ ring have nosubstituent other than an oxo group in the formulas);

L₃ is a C₂₋₃ alkylene group (more preferably, ethylene group) which mayhave 1 or 2 halogen atom(s), such as —(CH₂)₂—, —(CH₂)₃—, —CHFCH₂—,—CHF(CH₂)₂—, —CF₂CH₂— and —CF₂(CH₂)₂—;

L₂ is a C₂₋₄ alkylene group which may have 1 to 4 substituent(s)selected from halogen atom, hydroxy, oxo and phenyl, such as —(CH₂)₂—,—(CH₂)₃—, —CF₂CH₂—, —CF₂(CH₂)₂—, —(CH₃)CHCH₂—, —(CH₃)CH(CH₂)₂—,—CH₂CH(OH)—, —CH₂CO—, and -(Ph)CHCH₂— (more preferably, C₂₋₃ alkylenegroup which may have hydroxy, oxo or phenyl);

X is a bond, an oxygen atom or NH (more preferably, bond or oxygenatom);

Ar₂ is (1) (i) a C₆₋₁₀ aryl group (phenyl etc.) or (ii) a 5- or6-membered aromatic heterocyclic group (optionally condensed with abenzene ring) containing 1 to 4 hetero atom(s) selected from a nitrogenatom, an oxygen atom and a sulfur atom (e.g. thienyl, furyl, pyrrolyl,imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isooxazolyl,pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxadiazolyl, thiadiazolyl,furazanyl, indolyl, isoindolyl, benzofuranyl, quinolyl, isoquinolyl,naphthyridinyl, quinazolinyl, cinnolinyl, acridinyl etc.), each of whichmay have 1 to 5 (preferably 1 to 3) substituent(s) selected from halogen(fluoro, chloro etc.), C₁₋₆ alkyl (methyl, ethyl etc.), halogenoC₁₋₆alkyl (trifluoromethyl etc.), hydroxy, C₁₋₆ alkoxy (methoxy, ethoxyetc.), halogenoC₁₋₆ alkoxy (trifluoromethoxy, trifluoroethoxy etc.),nitro, amino, cyano, carbamoyl, carbamoyl which may be substituted withC₁₋₆alkyl or amino which may be substituted with formyl (NHCHO, NHCONH₂,NHCONHMe etc.), C₁₋₃ alkylenedioxy (methylenedioxy etc.), anaminocarbonyloxy group which may be substituted with C₁₋₆ alkyl(aminocarbonyloxy, methylaminocarbonyloxy, ethylaminocarbonyloxy,dimethylaminocarbonyloxy, diethylaminocarbonyloxy etc.), 5- to7-membered cyclic amino-carbonyloxy ((1-pyrrolidinyl)carbonyloxy,piperidinocarbonyloxy etc.), aminosulfonyl, mono-C₁₋₆ alkylaminosulfonyland di-C₁₋₆ alkylaminosulfonyl (more preferably, (i) a C₆₋₁₀ aryl group(phenyl etc.) or (ii) a 5- or 6-membered aromatic heterocyclic group(optionally condensed with a benzene ring) containing 1 to 4 heteroatom(s) selected from a nitrogen atom, an oxygen atom and a sulfur atom(thienyl, indolyl etc.), each of which may have 1 to 3 substituent(s)selected from halogen, nitro, hydroxy, optionally halogenated C₁₋₆alkyl, optionally halogenated C₁₋₆ alkoxy and aminosulfonyl, or (2) Ar₂and L₂ are linked together to form a ring represented by the formula:

wherein symbols are as defined above.

In addition, among Compound (I), a compound represented by the formula:

wherein Ar₄ represents a benzene ring group which has 1 or 2substituent(s) selected from aminosulfonyl, mono-or di-C₁₋₆alkylaminosulfonyl, C₁₋₆ alkyl-carbonylamino and C₁₋₆alkylsulfonylamino, and further may have 1 to 4 substituent(s), and theother symbols are as defined above (hereinafter, abbreviated as Compound(Ic) in some cases) or a salt thereof is a novel compound.

The “substituent” in the “benzene ring group further may have 1 to 4substituent(s)” represented by Ar₄ include the same groups as thoseexemplified with respect to the “substituent” in the “represents anoptionally condensed 5- or 6-membered aromatic ring group, and saidaromatic ring group may have a substituent” represented by Ar (providedthat aminosulfonyl, mono-or di-C₁₋₆ alkylaminosulfonyl, C₁₋₆alkyl-carbonylamino and C₁₋₆ alkylsulfonylamino are excluded).

Compound (Ic) is preferably a compound wherein Ar₄ is a benzene ringgroup which has 1 or 2 (more preferably 1) substituent(s) selected fromaminosulfonyl, mono- or di-C₁₋₆ alkylaminosulfonyl, C₁₋₆alkyl-carbonylamino and C₁₋₆ alkylsulfonylamino, and further may have 1or 2 (more preferably 1) C₁₋₄ alkoxy;

L₁ is a C₄₋₅ alkylene group which may have 1 or 2 halogen atom(s)(preferably, unsubstituted C₄₋₅ alkylene group), such as —(CH₂)₄—,—(CH₂)₅—, —CHF(CH₂)₃—, —CHF(CH₂)₄—, —CF₂(CH₂)₃—, —CF₂(CH₂)₄—,—(CH₂)₃CH(CH₃)—, and —(CH₂)₄CH(CH₃)—;

R is (i) a hydrogen atom, (ii) a C₁₋₄ alkyl group which may have 1 to 3substituent(s) selected from halogen atom (preferably fluoro etc.) andhydroxy, or (iii) a C₇₋₁₆ aralkyl (benzyl etc.) (more preferably,hydrogen atom or C₁₋₄ alkyl group);

L₂ is a C₂₋₄ alkylene group which may have 1 to 4 substituent (s)selected from halogen atom, hydroxy, oxo, and phenyl (e.g. —(CH₂)₂—,—(CH₂)₃—, —(CH₂)₄—, —CHFCH₂—, —CHF(CH₂)₂—, —CHF(CH₂)₃—, —CF₂CH₂—,—CF₂(CH₂)₂—, —CF₂(CH₂)₃—, —(CH₃)CHCH₂—, —(CH₃)CH(CH₂)₂—, —(CH(CH₃))₂—,—CH₂CH(OH)—, —CH₂CO—, -(Ph)CHCH₂— etc.) (more preferably, C₂₋₃ alkylenegroup which may have hydroxy or oxo);

X is a bond, an oxygen atom or NH (more preferably a bond);

Ar₂ is (1) (i) a C₆₋₁₀ aryl group (phenyl etc.) or (ii) a 5- or6-membered aromatic heterocyclic group (optionally condensed with abenzene ring) containing 1 to 4 hetero atom(s) selected from a nitrogenatom, an oxygen atom and a sulfur atom (e.g. thienyl, furyl, pyrrolyl,imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isooxazolyl,pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxadiazolyl, thiadiazolyl,furazanyl, indolyl, isoindolyl, benzofuranyl, quinolyl, isoquinolyl,naphthyridinyl, quinazolinyl, cinnolinyl, acridinyl etc.), each of whichmay have 1 to 5 (preferably 1 to 3) substituent(s) selected from halogen(fluoro, chloro etc.), C₁₋₆ alkyl (methyl, ethyl etc.), halogenoC₁₋₆alkyl (trifluoromethyl etc.), hydroxy, C₁₋₆ alkoxy (methoxy, ethoxyetc.), halogenoC₁₋₆ alkoxy (trifluoromethoxy, trifluoroethoxy etc.),nitro, amino, cyano, carbamoyl, carbamoyl which may be substituted withC₁₋₆ alkyl or amino which may be substituted with formyl (NHCHO,NHCONH₂, NHCONHMe etc.), C₁₋₃ alkylenedioxy (methylenedioxy etc.), anaminocarbonyloxy group which may be substituted with C₁₋₆ alkyl(aminocarbonyloxy, methylaminocarbonyloxy, ethylaminocarbonyloxy,dimethylaminocarbonyloxy, diethylaminocarbonyloxy etc.), 5- to7-membered cyclic amino-carbonyloxy ((1-pyrrolidinyl)carbonyloxy,piperidinocarbonyloxy etc.), aminosulfonyl, mono-C₁₋₆ alkylaminosulfonyland di-C₁₋₆ alkylaminosulfonyl, (2) the case where Ar₂ and R are linkedtogether to form a ring represented by the formula:

wherein symbols are as defined above, or (3) the case where Ar₂ and L₂are linked together to form a ring represented by the formula:

wherein symbols are as defined above (Ar₂ is more preferably (i) a C₆₋₁₀aryl group (phenyl etc.) or (ii) a 5- or 6-membered aromaticheterocyclic group (optionally condensed with a benzene ring) containing1 to 4 hetero atom(s) selected from a nitrogen atom, an oxygen atom anda sulfur atom (thienyl, indolyl etc.), each of which may have. 1 to 3substituent(s) selected from halogen, nitro, hydroxy, optionallyhalogenated C₁₋₆ alkyl, optionally halogenated C₁₋₆ alkoxy andaminosulfonyl).

In addition, among Compound (I), a compound represented by the formula:

wherein n represents an integer of 1 or 2, L₄ represents a C₃₋₅ alkylenegroup which may have a substituent, and the other symbols are as definedabove (hereinafter, abbreviated as Compound (Id) in some cases) or asalt thereof is a novel compound.

Examples of the “C₃₋₅ alkylene group which may have a substituent”represented by L₄ include those having a carbon chain number of 3 to 5among the “C₁₋₁₀ alkylene group” exemplified with respect to the “spacerhaving a main chain of 1 to 10 atoms which may have a substituent”represented by L.

The “substituent” in the “C₃₋₅ alkylene group which may have asubstituent” represented by L₄ include the same groups as thoseexemplified with respect to the “substituent” in the “spacer having amain chain of 1 to 10 atoms which may have a substituent” represented byL. Preferable examples include 1 to 4 substituent(s) selected fromhalogen atom (e.g. fluorine, chlorine, bromine,iodine etc.), nitro,cyano, optionally halogenated C₁₋₆ alkoxy, and hydroxy.

Compound (Id) is preferably a compound wherein R¹ and R^(1′) are ahydrogen atom or an optionally halogenated C₁₋₆ alkyl group (methyl,ethyl, trifluoromethyl etc.);

L₄ is a C₃₋₅ alkylene group (more preferably C₃₋₄ alkylene group) whichmay have 1 or 2 halogen atom(s), such as —(CH₂)₃—, —(CH₂)₄—, —(CH₂)₅—,—CHF(CH₂)₂—, —CHF(CH₂)₃—, —CF₂(CH₂)₂—, —CF₂(CH₂)₃—, —(CH₂)₂CH(CH₃)—, and—(CH₂)₃CH(CH₃)—);

R is (i) a hydrogen atom, (ii) a C₁₋₄ alkyl group which may have 1 to 3substituent(s) selected from halogen atom (preferably fluoro etc.) andhydroxy, or (iii) C₇₋₁₆ aralkyl (benzyl etc.) (more preferably ahydrogen atom or a C₁₋₄ alkyl group);

L₂ is a C₂₋₄ alkylene group which may have 1 to 4 substituent(s)selected from halogen atom, hydroxy, oxo, and phenyl (e.g. —(CH₂)₂—,—(CH₂)₃—, —(CH₂)₄—, —CHFCH₂—, —CHF(CH₂)₂—, —CHF(CH₂)₃—, —CF₂CH₂—,—CF₂(CH₂)₂—, —CF₂(CH₂)₃—, —(CH₃)CHCH₂—, —(CH₃)CH(CH₂)₂—. —(CH(CH₃))₂—,—CH₂CH(OH)—, —CH₂CO—, -(Ph)CHCH₂— etc.) (more preferably C₂₋₃ alkylenegroup which may have hydroxy or oxo);

X is a bond, an oxygen atom or NH (more preferably a bond);

Ar₂ is (1) (i) a C₆₋₁₀ aryl group (phenyl etc.) or (ii) a 5- or6-membered aromatic heterocyclic group (optionally condensed with abenzene ring) containing 1 to 4 hetero atom(s) selected from a nitrogenatom, an oxygen atom and a sulfur atom (e.g. thienyl, furyl, pyrrolyl,imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxadiazolyl,thiadiazolyl, furazanyl, indolyl, isoindolyl, benzofuranyl, quinolyl,isoquinolyl, naphthyridinyl, quinazolinyl, cinnolinyl, acridinyl etc.),each of which may have 1 to 5 (preferably 1 to 3) substituent(s)selected from halogen (fluoro, chloro etc.), C₁₋₆ alkyl (methyl, ethyletc.), halogenoC₁₋₆ alkyl (trifluoromethyl etc.), hydroxy, C₁₋₆ alkoxy(methoxy, ethoxy etc.), halogenoC₁₋₆ alkoxy (trifluoromethoxy,trifluoroethoxy etc.), nitro, amino, cyano, carbamoyl, carbamoyl whichmay be substituted with C₁₋₆ alkyl or amino which may be substitutedwith formyl (NHCHO, NHCONH₂, NHCONHMe etc.), C₁₋₃ alkylenedioxy(methylenedioxy etc.), an aminocarbonyloxy group which may besubstituted with C₁₋₆ alkyl (aminocarbonyloxy, methylaminocarbonyloxy,ethylaminocarbonyloxy, dimethylaminocarbonyloxy, diethylaminocarbonyloxyetc.), 5- to 7-membered cyclic amino-carbonyloxy((1-pyrrolidinyl)carbonyloxy, piperidinocarbonyloxy etc.),aminosulfonyl, mono-C₁₋₆ alkylaminosulfonyl and di-C₁₋₆alkylaminosulfonyl, (2) the case where Ar₂ and R are linked together toform a ring represented by the formula:

wherein symbols are as defined above, or (3) the case where Ar₂ and L₂are linked together to form a ring represented by the formula:

wherein symbols are as defined above (Ar₂ is more preferably (i) a C₆₋₁₀aryl group (phenyl etc.) or (ii) a 5- or 6-membered aromaticheterocyclic group (optionally condensed with a benzene ring) containing1 to 4 hetero atom(s) selected from a nitrogen atom, an oxygen atom anda sulfur atom (thienyl, indolyl etc.), each of which may have 1 to 3substituent(s) selected from halogen, nitro, hydroxy, optionallyhalogenated C₁₋₆ alkyl, optionally halogenated C₁₋₆ alkoxy andaminosulfonyl).

When Compound(I), (Ia), (Ib), (Ic) or (Id) (hereinafter, referred to asCompound B) is a salt, examples of such salt include salts with aninorganic base, an ammonium salt, salts with an organic base, salts withan inorganic acid, salts with an organic acid, an salts with a basic oracidic amino acid.

Preferable examples of the salt with an inorganic base include alkalimetal salts such as a sodium salt and a potassium salt; alkaline earthmetal salts such as a calcium salt, a magnesium salt and a barium salt;an aluminum salt.

Preferable examples of the salt with an organic base include salts withtrimethylamine, triethylamine, pyridine, picoline, ethanolamine,diethanolamine, triethanolamine, dicyclohexylamine, andN,N-dibenzylethylenediamine.

Preferable examples of the salt with an inorganic acid include saltswith hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid andphosphoric acid.

Preferable examples of the salt with an organic acid include salts withformic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalicacid, tartaric acid, maleic acid, citric acid, succinic acid, malicacid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonicacid.

Preferable examples of the salt with a basic amino acid include saltswith arginine, lysine and ornithine, and preferable examples of the saltwith an acidic amino acid include aspartic acid and glutamic acid.

Among these salts, pharmaceutically acceptable salts are preferred. Forexample, when Compound B has an acidic functional group, it may be aninorganic salt such as an alkali metal salt (e.g. sodium salt, potassiumsalt etc.), and an alkaline earth metal salt (e.g. calcium salt,magnesium salt, barium salt etc.), or an ammonium salt. When Compound Bhas a basic functional group, it may be an inorganic salt such ashydrochloride, sulfate, phosphate and hydrobromide; or an organic saltsuch as acetate, maleate, fumarate, succinate, methanesulfonate,p-toluenesulfonate, citrate, and tartarate.

Compound B may be an anhydride or a hydrate. In the case of a hydrate,Compound B may have 0.1 to 5 of water molecules.

Further, Compound B may be labeled with an isotope element (e.g. ³H,¹⁴C, ³⁵S etc.).

When Compound B contains an optical isomer, a steric isomer, apositional isomer or a rotational isomer, these are also included in thecompound of the present invention, and each of the isomers may beobtained as a single compound by a synthetic method or separation methodknown per se. For example, when Compound B has an optical isomer, anoptical isomer resolved from the compound is included in Compound B.

The optical isomer can be prepared by a method known per se.Specifically, an optically active isomer can be obtained by using anoptically active compound in the synthesis, or optically resolving thefinal mixture of racemic isomers with a conventional method.

As an optical resolution method, a method known per se, for example, afractional recrystallization method, a chiral column method and adiastereomer method which will be described in detail below, is used.

1) Fractional Recrystallization Method

A method of obtaining a free optical isomer by forming a salt of aracemic compound and an optically active compound (e.g. (+)-mandelicacid, (−)-mandelic acid, (+)-tartaric acid, (−)-tartaric acid,(+)-1-phenethylamine, (−)-1-phenethylamine, cinchonine,(−)-cinchonidine, brucine etc), separating this by a fractionalrecrystallization method and, if necessary, via a neutralizing step.

2) A Chiral Column Method

A method for separating a racemic compound or a salt thereof by applyingto an optical isomer separating column (chiral column). For example, inthe case of liquid chromatography, optical isomers are separated byadding a mixture of optical isomers to a chiral column such asENANTIO-OVM (manufactured by Toso) or CHIRAL series manufactured byDaicel, and developing this with water, various buffers (e.g. phosphatebuffer), or an organic solvent (e.g. ethanol, methanol, isopropanol,acetonitrile, trifluoroacetic acid, diethylamine) alone or a mixturethereof. In addition, in the case of gas chromatography, optical isomersare separated by using a chiral column such as CP-Chirasil-DeXCB(manufactured by GL Science).

3) A Diastereomer Method

A method of obtaining an optical isomer by chemically reacting a mixtureof racemic compounds with an optically active reagent to give a mixtureof diastereomers, separating single substance with usual separationmeans (e.g. fractional recrystallization, chromatography method etc.)and separating off an optically active reagent moiety by chemicaltreatment such as hydrolyzation reaction. For example, when Compound Bhas hydroxy or primary or secondary amino in a molecule, a diastereomerof ester or amido can be obtained by subjecting the compound and anoptically active organic acid (e.g. MTPA[α-methoxy-α-(trifluoromethyl)phenylacetic acid], (−)-menthoxyaceticacid, etc.) to a condensation reaction. On the other hand, when CompoundB has a carboxylic acid group, a diastereomer of amido or ester isobtained by subjecting the compound and an optically active amine oralcohol reagent to a condensation reaction. The separated diastereomeris converted into an optical isomer of the original compound bysubjecting to acid hydrolysis or base hydrolysis reaction.

A prodrug of Compound B refers to a compound which is converted intoCompound B by a reaction with an enzyme or gastric acid under aphysiological condition in vivo, that is, a compound which is changed toCompound B by enzymatic oxidation, reduction or hydrolysis, and acompound which is changed into Compound B by hydrolysis with gastricacid. Examples of a prodrug of Compound B include a compound in which anamino group of Compound B is acylated, alkylated or phosphorylated [e.g.compound in which an amino group of Compound B is eicosanoylated,alanylated, pentylaminocarbonylated,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated,tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated, ortert-butylated]; a compound in which a hydroxy group of Compound B isacylated, alkylated, phosphorylated or converted into borate (e.g.compound in which a hydroxy group of Compound B is acetylated,palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated,alanylated, or dimethylaminomethylcarbonylated); a compound in which acarboxyl group of Compound B is esterified or amidated (e.g. compound inwhich a carboxyl group of Compound B is ethyl esterified, phenylesterified, carboxymethyl esterified, dimethylaminomethyl esterified,pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified,phthalidyl esterified, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methylesterified, cyclohexyloxycarbonylethyl esterified, or methylamidated).These compounds can be prepared from Compound B with a method known perse.

A prodrug of Compound B may be a compound which is converted intoCompound B under physiological conditions as described in “Developmentof Drugs”, Volume 7, Molecular Design, Hirokawa Shoten, 1990; pages163–198.

Then, a process for preparing Compound (Ia), (Ib), (Ic) and (Id) will bedescribed. Compound (I) is prepared according to the process forpreparing (Ia), (Ib), (Ic) and (Id) below.

Compounds (Ia), (Ic) and (Id) are prepared, for example, by a method ofthe following [Process A] or [Process B], and Compound (Ib) is prepared,for example, by the following [Process C]. In [Process A] to [ProcessC], when an alkylation reaction, a hydrolyzation reaction, an aminationreaction, an esterification reaction, an amidation reaction, anesterification reaction, an etherification reaction, an oxidizationreaction, a reduction reaction, and a reductive amination reaction arecarried out, these reactions are performed according to a method knownper se. Examples of these methods include the methods described inORGANIC FUNCTIONAL GROUP PREPARATIONS, 2^(nd) edition, ACADEMIC PRESSINC., 1989; Comprehensive Organic Transformations, VCH Publishers Inc.,1989.

In the following processes, Compounds (II), (II′), (II″), (III), (IV),(V), (VI), (VI′), (VI″), (VII), (VIII), (IX), (X), (XI), (XII), (XIII),(XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX) and (XXI) may form asalt, respectively. As the “salt”, for example, the “salt” of theaforementioned “when Compound B is a salt” can be applied.

[Process A] Process for Preparing Compound (Ia), (Ic) or (Id) by aCoupling Reaction of Compound (II), (II′) or (II″) with Compound (III).

wherein Z₁ represents a leaving group, and other respective symbols areas defined above.

As the “leaving group” represented by Z₁, for example, halogen atom(e.g. chloro, bromo, iodo), C₁₋₆ alkylsulfonyloxy (e.g.methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy), andC₆₋₁₀ arylsulfonyloxy (e.g. benzenesulfonyloxy, p-toluenesulfonyloxy)are used. In particular, halogen atom (e.g. chloro, bromo etc.), andmethanesulfonyloxy are preferable.

The present coupling reaction can be carried out without a solvent, orby dissolving or suspending the compounds in a suitable solvent such asa hydrocarbon solvent, an alcohol solvent, an ether solvent, ahalogenated hydrocarbon solvent, an aromatic solvent, a nitrile solvent,an amide solvent, a ketone solvent, a sulfoxide solvent, carboxylic acidsolvent, or water. These solvents may be used by mixing two or more atan appropriate ratio. Preferably, no solvent, or an alcohol solvent suchas ethanol, an aromatic solvent such as toluene, or an amide solventsuch as dimethylformamide is used.

The present coupling reaction may be carried out by adding a suitablebase. Alternatively, the base can be used as a solvent.

Examples of the “Base” Include:

1) strong basis such as hydride of an alkali metal or an alkaline earthmetal (e.g. lithium hydride, sodium hydride, potassium hydride, calciumhydride etc.), amides of an alkali metal or an alkaline earth metal(e.g. lithium amide, sodium amide, lithium diisopropylamide, lithiumdicyclohexylamide, lithium hexamethyldisilazide, sodiumhexamethyldisilazide, potassium hexamethyldisilazide etc.), and loweralkoxide of an alkali metal or an alkaline earth metal (e.g. sodiummethoxide, sodium ethoxide, potassium tert-butoxide etc.);

2) inorganic bases such as hydroxide of an alkali metal or an alkalineearth metal (e.g. sodium hydroxide, potassium hydroxide, lithiumhydroxide, barium hydroxide etc.), carbonate of an alkali metal or analkaline earth metal (e.g. sodium carbonate, potassium carbonate, cesiumcarbonate etc.), and bicarbonate of an alkali metal or an alkaline earthmetal (e.g. sodium bicarbonate, potassium bicarbonate); and

3) organic bases such as amines such as triethylamine,diisopropylethylamine, and N-methylmorpholine; amidines such as DBU(1,8-diazabicyclo[5.4.0]undec-7-ene), and DBN(1,5-diazabicyclo[4,3,0]non-5-ene); basic heterocyclic compounds such aspyridine, dimethylaminopyridine, imidazole, and 2,6-lutidine.

As the “base”, alkali metal salts such as potassium carbonate, andamines such as triethylamine and diisopropylethylamine are preferable.

Upon the present coupling reaction, a hydrogen atom of Compound (III)may be substituted with a metal atom, for example, an alkali metal suchas lithium and sodium in advance.

The present coupling reaction can be carried out at −100° C. to 300° C.,preferably 0° C. to 150° C. A reaction time is 1 minute to 1 day.

The present coupling reaction can be carried out at an arbitrary ratioof Compound (II), (II′) or (II″) and Compound (III), and either of themmay be used as a solvent.

Compound (III) can be prepared by a method known per se or a similarmethod thereto. For example, Compound (III) can be prepared by themethod described in Comprehensive Organic Transformation VIH PublishersInc., 1989, more specifically, the method described in J. Org. Chem.24,1106(1959), Bull. Chem. Soc. Jpn. 63,1252(1990), Synth. Commun. 14,1099(1984), Tetrahedron 49, 1807(1993), J. Heterociclic Chem. 28,1587(1991), J. Org. Chem. 60, 7086(1995) or a similar method thereto.

Compound (II) or (II′) can be prepared, for example, by a method such asFriedel-Crafts reaction shown below.

wherein Z₂ represents a leaving group, and the other respective symbolsare as defined above.

As the “leaving group” represented by Z₂, the same leaving groups asthose for the above-mentioned Z₁ can be applied. Preferred is a halogenatom (e.g. chloro, bromo etc.) or a hydroxy group.

The present reaction can be preferably carried out by adding an acidcatalyst, but the reaction can be carried out without adding an acidcatalyst. As the acid catalyst used in the reaction, mineral acids suchas sulfuric acid, phosphoric anhydride, and polyphosphoric acid, andLewis acids such as aluminum chloride, tin tetrachloride, titaniumtetrachloride, boron trifuloride, triethylaluminum, diethylaluminumchloride, and zinc chloride can be used. Preferable examples includepolyphosphoric acid, aluminum chloride, diethylaluminum chloride, andzinc chloride. An acid catalyst can be used at an arbitrary equivalent,usually, 0.1 equivalent to 10 equivalent relative to Compound (IV) orCompound (V). Occasionally, an acid catalyst can be used as a solvent.

The present reaction can be carried out without a solvent, or bydissolving or suspending reactants in a suitable solvent such as ahydrocarbon solvent, an ether solvent a halogenated hydrocarbon solvent,a nitrated hydrocarbon solvent, an aromatic solvent, a nitrile solvent,an amide solvent, a ketone solvent, a sufoxide solvent, and a carboxylicacid solvent. These may be used by mixing two or more at an appropriateratio. Preferably, for example, no solvent, or a halogenated hydrocarbonsolvent such as dichloromethane and 1,2-dichlroethane, a nitratedhydrocarbon solvent such as nitromethane, an aromatic solvent such asnitrobenzene, and carbon disulfide are used.

The present reaction can be carried out at −100° C. to 300° C. and,usually, 0° C. to 150° C. is preferable. A reaction time is, forexample, 1 minute to 3 days.

The present reaction can be carried out at an arbitrary ratio ofCompound (IV) and Compound (V), and either of them can be also used as asolvent.

Compound (IV) can be prepared by a method known per se or a similarmethod thereto. Compound (IV) can be prepared by the method, forexample, described in Synthesis 10, 862 (1984), J. Chem. Soc. 1518(1964), Synthesis 851 (1984), and JP-A No. 9-124605 or a similar methodthereto.

Compound (V) can be prepared by a method known per se or a similarmethod thereto. Compound (V) can be prepared by the method, for example,described in Org. Syn. Coll. Vol. 1, 12 (1941), Helv. Chem. Acta 42,1653 (1959) or a similar method thereto.

Compound (II) or (II′) can be prepared by a method other than theaforementioned Friedel-Crafts reaction. Examples of the “method otherthan the Friedel-Crafts reaction” include a method using an organicmetal reagent such as a method using an arylmagnesium reagent describedin Tetrahedron Lett. 27, 929(1986), J. Am. Chem. Soc. 70, 426 (1948),Synlett 3, 225 (1996), a method using an organic zinc reagent describedin Tetrahedron 46, 6061(1990). Alternatively, for example, Compound (II)or (II′) can be prepared using a method for synthesis from an activemethylene derivative described in JP-A 3-95143.

Compound (II″) can be prepared, for example, by a method of introducinga substituent V into Compound (XII) to obtain Compound (XIII), couplingCompound (XIII) and Compound (XIV), and removing the substituent V asshown below:

wherein substituent V represents an electron withdrawing group, Z₃represents a leaving group, and the other respective symbols are asdefined above.

As the “electron withdrawing group” represented by the substituent V,for example, a C₁₋₈ alkoxycarbonyl group (e.g. methoxycarbonyl,tert-butoxycarbonyl group etc.), a C₇₋₁₆ aralkyloxycarbonyl group (e.g.benzyloxycarbonyl group etc.), a carboxyl group, and a cyano group areused. Preferable is a C₁₋₄ alkoxycarbonyl group (e.g. methoxycarbonyl,tert-butoxycarbonyl group etc.).

As the “leaving group” represented by Z₃, the same leaving groups asthose for the above-mentioned Z₁ can be applied. Preferred is a halogenatom (e.g. chloro, bromo etc.), a p-toluenesulfonyloxy group or amethanesulfonyloxy group.

The reaction of “introducing a substituent V” can be carried out withoutsolvent, or in a suitable solvent. As the “solvent”, the same solventsas “solvents” described for the above-mentioned Process A can be used.For example, no solvent, or an ether solvent such as tetrahydrofuran, anaromatic solvent such as toluene, and an amide solvent such asdimethylformamide are preferred.

As a precusor of the substituent V in the present reaction “ofintroducing a substituent V”, for example, carbonic acid ester (dimethylcarbonate etc.), halocarbonic acid ester (methyl chlorocarbonate) orcarbon dioxide is used.

Alternatively, the present reaction “of introducing a substituent V” maybe carried out by adding an appropriate base. In addition, the base maybe used as a solvent. As the, “base”, the same bases as “bases”described for the above-mentioned Process A can be used. For example,sodium hydride, sodium amide, and lithium diisopropylamide arepreferred.

The present reaction “of introducing a substituent V” can be carried outat −100° C. to 300° C., and 0° C. to 150° C. is preferred. A reactiontime is, for example, 1 minute to 1 day.

The coupling reaction of Compound (XIII) and Compound (XIV) can becarried out without solvent or in a suitable solvent. As the “solvent”,the same solvents as “solvents” described for the above-mentionedProcess A can be used. For example, no solvent, or an ether solvent suchas tetrahydrofuran, an aromatic solvent such as toluene, and an amidesolvent such as dimethylformamide are preferred.

Alternatively, the present “coupling reaction of Compound (XIII) andCompound (XIV)” may be carried out by adding an appropriate base. Inaddition, the base may be used as a solvent. As the “base”, the samebases as “bases” described for the above-mentioned Process. A can beused. For example, sodium hydride, sodium amide, and lithium diisopropylamide are preferable.

The present “coupling reaction of Compound (XIII) and Compound (XIV)”can be carried out at −100° C. to 300° C., and 0° C. to 150° C. ispreferred. A reaction time is, for example, 1 minute to 1 day.

A reaction “of removing a substituent V” can be carried out withoutsolvent or in a suitable solvent. As the “solvent”, the same solvents as“solvents” described for the above-mentioned Process A can be used. Forexample, no solvent, or an ether solvent such as diglyme, an aromaticsolvent such as xylene, a sulfoxide solvent such as dimethyl sulfoxide,and water are preferred.

Alternatively, the present reaction “of removing a substituent V” may becarried out by adding an appropriate acid or salt. In addition, the acidmay be used also as a solvent. As the “acid”, a mineral acid such ashydrochloric acid and sulfuric acid, and p-toluenesulfonic acid arepreferred. As the “salt”, for example, sodium chloride is used.

The present reaction “of removing a substituent” is preferably carriedout by heating. Preferably, the reaction is carried out at roomtemperature to 250° C. A reaction time is, for example, 1 minute to 1day.

Compound (XII) can be prepared according to the method, for example,described in J. Org. Chem. 36, 2480, (1971). That is, for example, asshown below, Compound (XII) can be prepared by a method of preparingCompound (XVIII) by Friedel-Crafts reaction of Compound (XVI) andCompound (XVII), converting Compound (XVIII) into Compound (XIX) byreduction reaction, followed by halogenation to obtain Compound (XX),and carrying out intramolecular Friedel-Crafts reaction. Alternatively,Compound (XII) may be also prepared by intramolecular Friedel-Craftsreaction of Compound (XIX).

Alternatively, Compound (XII) can be prepared, for example, according tothe method of Org. Syn. Coll. Vol. 4, 898(1963). That is, for example,Compound (XII) can be prepared by tandem-type intramolecularFriedel-Crafts reaction of Compound (XVI) and Compound (XXI) as shownbelow:

wherein respective symbols as defined above.

The “Friedel-Crafts:reaction of Compound (XVI) and Compound (XVII)” canbe carried out by a method according to the aforementioned“Friedel-Crafts reaction of Compound (IV) and Compound (X)”. In the“reduction” reaction of Compound (XVII) to compound (XIX), catalyticreduction using, for example, a palladium catalyst, Clemmensenreduction, for example, described in Org. React. 22, 401 (1975), andWolff-Kishner reduction, for example, described in, Org. React. 4,378(1948) can be used.

The “halogenation” reaction of Compound (XIX) to Compound (XX) iscarried out by using a reagent used for halogenation such as thionylchloride, oxalyl chloride, and chlorine. Alternatively, a halogenationreagent may be used as a solvent.

The “intramolecular Friedel-Crafts reaction” from Compound (XIX) toCompound (XII) can be carried out by a method according to theaforementioned “Friedel-Crafts reaction of Compound (IV) and Compound(X)”. As Lewis acid, polyphosphoric acid is preferable.

The “intramolecular Friedel-Crafts reaction” from Compound (XX) toCompound (XII) can be carried out by a mouthed according to theaforementioned “Friedel-Crafts reaction of Compound (IV) and Compound(X)”.

The preparation of Compound (XII) by the “tandem-type intramolecularFriedel-Crafts reaction” of Compound (XVI) and Compound (XXI) can becarried out by a method according to the aforementioned “Friedel-Craftsreaction of Compound (IV) and Compound (X)”.

[Process B] Process for Preparing Compound (Ia), (Ic) or (Id) by aCoupling Reaction of Compound (VI) or (VI′) and Compound (VII).

wherein respective symbols are as defined above.

The present coupling reaction can be carried out without a solvent, orin an appropriate solvent. As the “solvent”, the same solvents as“solvents” described for the above-mentioned Process A can be used. Forexample, no solvent, or an alcohol solvent such as ethanol, an aromaticsolvent such as toluene, and an amide solvent such as dimethylformamideare preferable.

Alternatively, the present coupling reaction may be carried out byadding an appropriate base. In addition, the base may be also used as asolvent. As the “base” the same bases as “bases” described for theabove-mentioned Process A can be used.

Upon the present coupling reaction, a hydrogen atom of Compound (VI) or(VI′) may be substituted with a metal atom, for example, an alkali metalsuch as lithium and sodium in advance.

The present coupling reaction may be carried out at −100° C. to 300° C.,and 0° C. to 150° C. is preferred. A reaction time is, for example, 1minute to 1 day.

The present coupling reaction can be carried out at an arbitrary ratioof Compound (VI) or (VI′) and Compound (VII), and either of them may beused also as a solvent.

Compound (VII) can be prepared by a method known per se or a similarmethod thereto.

Compound (VI), (VI′) or (VI″) can be prepared, for example, by acoupling reaction of the aforementioned Compound (II) or (II′) andCompound (VIII) as shown below.

wherein respective symbols are as defined above.

The present coupling reaction can be carried out without solvent or inan appropriate solvent. As the “solvent”, the same solvents as“solvents” described for the above-mentioned Process A can be used. Forexample, no solvent, or an alcohol solvent such as ethanol, an aromaticsolvent such as toluene, and an amide solvent such as dimethylformamideare preferable.

Alternatively, the present coupling reaction may be carried out byadding an appropriate base. In addition, the base may be used also as asolvent. As the “base”, the same bases as “bases” described for theabove-mentioned Process A can be used.

Upon the present coupling reaction, a hydrogen atom of Compound (VIII)may be substituted with a metal atom, for example, an alkali metal suchas lithium and sodium in advance.

The present coupling reaction can be carried out at −100° C. to 300° C.,and 0° C. to 150° C. is preferred. A reaction time is, for example, 1minute to 1 day.

The present coupling reaction can be carried out at an arbitrary ratioof Compound (II) or (II′) and Compound (VIII), and either of them may bealso used as a solvent.

Compound (VIII) can be prepared by a method known per se or a similarmethod thereto. For example, Compound (VIII) can be prepared by themethod described in Comprehensive Organic Transformation VCH PublishersInc., 1989, specifically, a reductive amination reaction described inOrganic Reactions (Org. Rxs.) 14, 52 (1965), Synthesis 30(1972), areduction reaction of nitrites described in Org. Rxs. 6, 469(1951),Chem. Pharm. Bull. 32, 873(1984), a reduction reaction of azidedescribed in J. Med. Chem. 12, 658(1969), J. Am. Chem. Soc. 73,5865(1951), and a Gabriel synthesis method described in Org. Syn. Coll.Vol. 2, 83(1943), J. Am. Chem. Soc. 72, 2786(1950).

[Process C] Process for Preparing Compound (Ib) by a Coupling Reactionof Compound (IX) and Compound (VII).

wherein respective symbols are as defined above.

The present coupling reaction can be carried out according to theaforementioned Process A. Specifically, the present reaction can becarried out without solvent, or in an appropriate solvent. As the“solvent”, the same solvents as “solvents” described for theabove-mentioned Process A can be used. For example, no solvent, or analcohol solvent such as ethanol, an aromatic solvent such as toluene, anitrile solvent such as acetonitrile, and an amide solvent such asdimethylformamide are preferable.

Alternatively, the present coupling reaction may be carried out byadding an appropriate base. In addition, the base may be also used as asolvent. As the “base”, the same bases as “bases” described for theabove-mentioned Process A can be used. Potassium carbonate,triethylamide, and diisopropylethylamine are preferred.

Upon the present coupling reaction, a hydrogen atom of Compound (IX) maybe substituted with a metal atom, for example, an alkali metal such aslithium and sodium in advance.

The present coupling reaction can be carried out at −100° C. to 300° C.,and 0° C. to 150° C. is preferred. A reaction time is, for example, 1minute to 1 day.

The present coupling reaction can be carried out at an arbitrary ratioof Compound (IX) and Compound (VII), and further either of them may bealso used as a solvent.

Compound (IX) can be prepared, for example, by a method such aspreparing Compound (XI) by Friedel-Crafts reaction of Compound (IV) andCompound (X), followed by subjecting to a deprotection reaction as shownbelow.

wherein W represents a protecting group for amine, and the otherrespective symbols are as defined above.

As the protecting group W for amine, for example, protecting groupsdescribed in Protective Groups in Organic Synthesis, Third Edition,Wiley-Interscience (1999) can be used. Specifically, examples thereofinclude acyl groups such as formyl, C₁₋₆ alkyl-carbonyl which may have asubstituent(e.g. acetyl, ethylcarbonyl, trifluoroacetyl, chloroacetyletc.), benzoyl, C₁₋₆ alkyl-oxycarbonyl (e.g. methoxycarbonyl,ethoxycarbonyl, t-butoxycarbonyl etc.), phenyloxycarbonyl (e.g.phenoxycarbonyl etc.), and C₇₋₁₅ aralkyloxy-carbonyl (e.g.benzyloxycarbonyl, fluorenyloxycarbonyl etc.), and hydrocarbon groupssuch as trityl and phthaloyl. Inter alia, acetyl, trifluoroacetyl andbenzyloxycarbonyl are preferred.

Z₂ is preferably a halogen atom (e.g. chloro, bromo etc.) or a hydroxygroup.

The Friedel Crafts reaction of Compound (IV) and Compound (X) can bepreferably carried out by adding an acid catalyst, and may be carriedout without adding an acid catalyst. As the acid catalyst used in thereaction, the same acid catalysts as those used in preparation of theabove-mentioned Compound (II) are used. Preferable examples includepolyphosphoric acid, aluminum chloride, diethylaluminum chloride, andzinc chloride. The acid catalyst can be used at an arbitrary equivalent,usually at 0.1 equivalent to 10 equivalents relative to Compound (IV) orCompound (X). Occasionally, the acid catalyst may be also used as asolvent.

As the solvent, same solvents as those used in preparation of theabove-mentioned Compound (II) can be applied. Preferable examplesinclude no solvent, or a halogenated hydrocarbon solvent such asdichloromethane, and 1,2-dichloroethane, a nitrated hydrocarbon solventsuch as nitromethane, an aromatic solvent such as nitrobenzene, andcarbon disulfide.

The present reaction can be carried out at −100° C. to 300° C. and,usually, 0° C. to 150° C. is preferred. A reaction time is, for example,1 minute to 3 days.

Deprotection of Compound (XI) can be carried out according to the methoddescribed in the aforementioned Protective Groups in Organic Synthesis,Third Edition, Wiley-Interscience (1999). Specifically, deprotection iscarried out by acid treatment, alkali hydrolysis, or catalytic reductionreaction.

Compound (X) can be prepared by a method known per se or a similarmethod thereto. For example, Compound (X) can be prepared by the methoddescribed in Chem. Pharm. Bull., 34, 3747 (1986), Chem. Pharm. Bull.,41, 529 (1993), and EP-A-0,378,207 or a similar method thereto.

When Compounds (Ia) to (Id) prepared by the aforementioned [Process A]to [Process C] are primary or secondary amine, those compounds can beisolated and purified after derived to other derivatives, if necessary.Preferable examples of “other derivatives” include compounds in whichthe primary or secondary amine is protected with a general amineprotecting group. Examples of the “general amine protecting group”include the protecting groups described in Protective Groups in OrganicSynthesis, Third Edition, Wiley-Interscience (1999). Specifically,examples include an acyl group such as formyl, C₁₋₆ alkyl-carbonyl whichmay have a substituent (e.g. acetyl, ethylcarbonyl etc.), benzoyl, C₁₋₆alkyl-oxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl,t-butoxycarbonyl etc.), phenyloxycarbonyl (e.g. phenoxycarbonyl etc.),and C₇₋₁₅ aralkyloxy-carbonyl (e.g. benzyloxycarbonyl,fluorenyloxycarbonyl etc.), and hydrocarbon groups such as trityl andphthaloyl. Preferably, an acetyl group, a benzoyl group, at-butoxycarbonyl group, a benzyloxycarbonyl group, and a benzyl groupare used. Purified “other derivatives” can be derived to the originalprimary or secondary amine or a salt thereof by a deprotection reactionsuitable for each of them. The “deprotection reaction” can be carriedout according to the method, for example, described in theaforementioned Protective Groups in Organic Synthesis, Third Edition,Wiley-Interscience (1999). Specifically, the deprotecting reaction iscarried out by acid treatment, alkaline hydrolysis, or catalyticreducing reaction.

As the “salt” in the “primary or secondary amine or a salt thereof”, the“salt” in the aforementioned “when Compound B is a salt” can be applied.

Compounds (Ia) to (Id) can be prepared by processes other than theaforementioned processes. For example, they may be prepared by reductiveamination reaction described in J. Am. Chem. Soc. 2897 (1971), Synthesis135 (1976), Tetrahedron Lett. 5595 (1990), an addition reaction of amineto epoxide described in Synth. Commun. 177 (1973), Tetrahedron Lett.4661 (1990), Michael addition reaction of amine to a conjugated doublebond described in Org. Rxs. 79 (1949), Organic Synthesis Coll. Vol. 1,196 (1941), a reduction reaction of amide described in Synthesis 752(1978), Org. Rxs. 303 (1942), or a Mannich reaction described in Org.Rxs. 469 (1941), Angew. Chem. 265 (1956).

Since Compound (A) and Compound (B) used in the present invention havelow toxity and exhibit excellent effects of improving an urine flow rateand a voiding efficiency and, at the same time, do not influence on avoiding pressure and a blood pressure, they can be used as a preventiveor therapeutic agent for voiding disturbance of a mammal such as humanand the like. For example, they can be used as a preventive ortherapeutic agent for voiding disturbance, in particular, voidingdifficulty derived from the following 1) to 7). 1) benign prostatichyperplasia, 2) bladder cervical atresia, 3) neurogenic bladder, 4)diabetes, 5) operation, 6) detrusor underactivity, and 7) Sjögren'ssyndrome (dry eye, dry mouth, vagina drying etc.).

More specifically, those compounds can be used as a preventive ortherapeutic agent for voiding difficulty due to detrusor underactivitydue to benign prostatic hyperplasia, detrusor underactivity due todiabetes, detrusor underactivity due to diabetic neuropathy, idiopathicdetrusor underactivity (including those due to aging), detrusorunderactivity due to multiple sclerosis, detrusor underactivity due toPerkinson's disease, detrusor underactivity due to spinal cord injury,detrusor underactivity after operation, detrusor underactivity due tocerebral infarction, neurogenic bladder due to diabetes, neurogenicbladder due to diabetic neuropathy, neurogenic bladder due to multiplesclerosis, neurogenic bladder due to Perkinson's disease, neurogenicbladder due to spinal cord injury, and neurogenic bladder due tocerebral infarction.

Further, Compound A and Compound B can be also used as a preventive ortherapeutic agent for urinary storage disturbance such as urinaryurgency due to overactive bladder, urinary frequency, detrusorunderactivity accompanied with overactive bladder, and urinaryincontinence.

In addition, Compound A and Compound B can be also used as a preventiveor therapeutic agent for glaucoma.

The present invention also provides a method for screening a compoundhaving effects of preventing or treating voiding disturbance or a saltthereof by Pressure Flow Study, which comprises using an animal modelloaded with an α agonist.

The screening method of the present invention can be performed bymeasuring influence of the test substance on voiding function of bladderof the animal model (maximum urine flow rate, intravesical pressure,voiding efficiency etc.) by Pressure Flow Study, in the case where atest substance is administered to an animal model loaded with an aagonist or the case where the test substance is not administered to theanimal model.

Examples of the “animal model” used in the screening method of thepresent invention include a non-human mammal such as a rabbit, a guiniapig, a hamster, a rat, a mouse, a gerbil, a dog and a monkey. Preferableexamples include a guinea pig (Hartley male guinea pig).

A week age, a body weight, the presence or absence of delivery of ananimal model used in the present invention is not particularly limitedas far as the model can be applied to the intended screening, and theseconditions may be appropriately changed.

An animal model loaded with an α-agonist (preferably phenylephrine) canbe prepared by a known method, for example, a method described in theaforementioned Non-Patent documents 3 to 5.

As a test substance, a tissue extract, and a cell culture supernatant ofa warm-blooded mammal (e.g. mouse, rat, pig, cow, sheep, monkey, humanetc.) are used in addition to a known synthetic compounds, peptides andproteins.

Measurement of voiding function (maximum urine flow rate, intravesicalpressure, voiding efficiency etc.) in the screening method of thepresent invention can be performed according to a known method, forexample, the method described in Non-Patent documents 6 to 9.

The screening method in the present invention can be usefully andeffectively applied to the screening of a compound having effects ofpreventing or treating voiding disturbance, in particular, voidingdisturbance accompanied with benign prostatic hyperplasia, and acompound having both of an acetylcholinesterase inhibitory action and anα₁ antagonistic action.

A preventive or therapeutic agent for voiding disturbance can beassessed by administering about 0.001 to about 1000 mg/kg (preferablyabout 0.01 to about 100 mg/kg) of a test substance to an animal modelloaded with an α agonist in the screening method of the presentinvention, and investigating therapeutic effects of the test substanceusing effects on a urine flow rate, an intravesical pressure, and avoiding efficiency as an index.

In addition, as an animal model used in the present invention, a normalanimal (animal exhibiting no pathology) may be used. However, forexample, the aforementioned voiding function of bladder may be measuredusing an animal exhibiting pathology such as voiding disturbance, benignprostatic hyperplasia, detrusor underactivity, overactive bladder,urinary frequency, urinary incontinence, diabetic neuropathy,hypertension, diabetes, obesity, hyperlipemia, arterial sclerosis,gastric ulcer, asthma, chronic obstructive respiratory disease, ovarycancer, cerebrovascular disease, brain injury, and spinal cord injury(e.g. obesity rat (Wistar Fatty rat)). When the aforementioned voidingfunction of bladder is measured in an animal exhibiting such pathology,this can be effectively applied to screening of a medical substance forpreventing or treating such the complex. However, this may be alsoapplied to screening of a medical substance which is effective only forthe aforementioned pathology (e.g. digestive tract disease such asgastric ulcer) and does not influence on voiding function, or may beapplied to screening for the purpose of excluding a test substance whichdoes not influence on voiding function from a medical substance to beselected.

Using this screening method, when a urine flow rate is improved by about20% or more and a voiding efficiency is improved by about 10% or more inthe case of administration of a test substance as compared with noadministration of the test substance, the test substance can bedetermined to a compound having effects of improving voiding function ora salt thereof (hereinafter, referred to as Compound C).

Compound A, B or C can be formulated into a preparation according tomeans known per se. The compound can be formulated into medicines suchas tablets (including sugar-coated tablets, film-coated tablets),powders, granules, capsules (including soft capsules), solutions,injectables, suppositories and sustained-release agents, as it is, or byappropriately mixing with an appropriate amount of a pharmacologicalacceptable carrier at a step of formulating into a preparation, and thecompound can be safely administered orally or parenterally (e.g.topically, rectally, intravenously etc.) as a preparation.

Examples of the pharmacologically acceptable carrier used in preparationof the medicine, or the preventive or therapeutic agent for voidingdisturbance of the present invention include various organic orinorganic carrier substances which are conventionally used as a pharmacymaterial, such as excipients, lubricants, binders and disintegratingagents in solid preparations; solvents, solubilizers, suspending agents,isotonics, buffers and soothing agents in liquid preparations. Ifnecessary, additives such as antiseptics, antioxidants, coloring agents,sweeteners, adsorbing agents, and wetting agents may be used.

Examples of the excipient include lactose, white sugar, D-mannitol,starch, corn starch, crystalline cellulose, and light silicic acidanhydride.

Examples of the lubricant include magnesium stearate, calcium stearate,talc, and colloidal silica.

Examples of the binder include crystalline cellulose, white sugar,D-mannitol, dextrin, hydroxypropylcellulose,hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose,gelatin, methylcellulose, and sodium carboxymethylcellulose.

Examples of the disintegrating agent include starch,carboxymethylcellulose, calcium carboxymethylcellulose, sodiumcarboxymethylstarch and L-hydroxypropylcellulose.

Examples of the solvent include water for injection, alcohol, propyleneglycol, macrogol, sesame oil, and corn oil.

Examples of the solubilizer include polyethylene glycol, propyleneglycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane,cholesterol, triethanolamine, sodium carbonate, and sodium citrate.

Examples of the suspending agent include surfactants such asstearyltriethanolamine, sodium laurylsulfate, laurylaminopropionic acid,lecithin, benzalkonium chloride, benzethonium chloride, and glycerinmonostearic acid; hydrophilic polymers such as polyvinyl alcohol,polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose,hydroxymethylcellulose, hydroxyethylcellulose, andhydroxypropylcellulose.

Examples of the isotonic include glucose, D-sorbitol, sodium chloride,glycerin, and D-mannitol.

Examples of the buffer include buffers such as phosphate, acetate,carbonate, and citrate.

Examples of the soothing agent include benzyl alcohol.

Examples of the antiseptic include paraoxybenzoic acid esters,chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid,and sorbic acid.

Examples of the antioxidant include sulfite, and ascorbic acid.

A content of Compound A, B or C used in the medicine, or the preventiveor therapeutic agent for voiding disturbance of the present invention isabout 0.1 to about 100% by weight based on a total weight of the agent.

A dose of the medicine, or the preventive or therapeutic agent forvoiding disturbance of the present invention differs depending on anadministration subject, an administration route, and disease. Forexample, the dosage of a therapeutic agent for voiding difficulty isabout 0.005 to 1000 mg, preferably about 0.05 to 500 mg, more preferablyabout 0.5 to 200 mg as one dose of active ingredient, as an oralpreparation for an adult (body weight about 60 kg). The preparation maybe administered once or by dividing a few times per day.

Compound A, B or C can be used in combination with a medicine fortreating disease causing voiding disturbance (e.g. voiding difficultyetc.) or a medicine which is administered for treating other disease butitself induces voiding disturbance (e.g. voiding difficulty etc.).

Examples of the “medicine for treating disease causing voidingdisturbance” include a therapeutic agent for benign prostatichyperplasia, a therapeutic agent for prostate cancer, a therapeuticagent for chronic cystitis, a therapeutic agent for constipation, atherapeutic agent for large intestine cancer, a therapeutic agent forovary cancer, a therapeutic agent for diabetes, a therapeutic agent forcerebrovascular disorder, a therapeutic agent for spinal cord injury, atherapeutic agent for spinal tumor, a therapeutic agent for multiplesclerosis, a therapeutic agent for dimentia including Alzheimer'sdisease, a therapeutic agent for Parkinson's disease, a therapeuticagent for progressive supranuclear palsy, a therapeutic agent forGuillain-Barre syndrome, a therapeutic agent for acute panautonomicabnormality, a therapeutic agent for olivotontocerebellar atrophy, and atherapeutic agent for cervical vertebrae disorder.

Examples of the therapeutic agent for benign prostatic hyperplasiainclude Allylestrenol, Chlormadinone acetate, Gestonorone caproate,Nomegestrol, Mepartricin, Finaststeried, PA-109, and THE-320. Inaddition, examples of the therapeutic agent for voiding disturbanceaccompanied with benign prostatic hyperplasia include α-reductaseinhibitors such as YM-31758, YM-32906, KF-20405, MK-0434, finasteride,and CS-891.

Examples of the therapeutic agent for prostate cancer includeIfosfamide, Estramustine phosphate sodium, Cyproterone, Chlormadinoneacetate, Flutamide, Cisplatin, Lonidamine, Peplomycin, Leuprorelin,Finasteride, Triptorelin-DDS, Buserelin, Goserelin-DDS, Fenretinide,Bicalutamide, Vinorelbine, Nilutamide, Leuprolide-DDS, Deslorelin,Cetrorelix, Ranpirnase, Leuprorelin-DDS, Satraplatin, Prinomastat,Exisulind, Buserelin-DDS, and Abarelix-DDS.

Examples of the therapeutic agent for chronic cystitis include Flavoxatehydrochloride.

Examples of the therapeutic agent for constipation include SennosideA•B, and Phenovalin.

Examples of the therapeutic agent for large intestine cancer includeChromomycin A3, Fluorouracil, Tegafur and Krestin.

Examples of the therapeutic agent for ovary cancer include ChromomycinA3, Fluorouracil, Bleomycin hydrochloride, and Medroxyprogesteroneacetate.

Examples of the therapeutic agent for diabetes include Insulinresistance improving drug, Insulin secretion accelerating drug,biguanide agent, Insulin, α-Glucosidase inhibitor, and β3 adrenalinereceptor agonist.

Examples of the Insulin resistance improving drug include pioglitazoneor a salt thereof (preferably hydrochloride), troglitazone,rosiglitazone or a salt thereof (preferably maleate), JTT-501,GI-262570, MCC-555, YM-440, DRF-2593, BM-13-1258, KRP-297, and CS-011.

Examples of the Insulin secretion accelerating drug include sulfonylureapreparation. Specific examples of the sulfonylurea preparation includetolbutamide, chloropropamide, tolazamide, acetohexamide, glyclopyramideand an ammonium salt thereof, glibenclamide, gliclazid, and glimepiride.Besides, examples of the Insulin secretion accelerating drug includerepaglinide, nateglinide, KAD-1229, and JTT-608.

Examples of the biguanide agent include metformin and buformin.

Examples of the Insulin include animal Insulin extracted from cattle,pig pancreas; semi-synthetic human Insulin enzymatically syntesized fromInsulin extracted from pig pancreas, human Insulin synthesized bygenetic engineering using Escherichia coli or yeast. As the Insulin,Insulin zinc including 0.45 to 0.9 (w/w) % of zinc; Protamineinsulinzinc prepared from zinc chloride, protamine sulfate and Insulin areused. Further, Insulin may be a fragment or derivative thereof (e.g.INS-1 etc.).

Examples of the α-Glucosidase inhibitor include acarbose, voglibose,miglitole, and emiglitate.

Examples of the β3 adrenaline receptor agonist include AJ-9677,BMS-196085, SB-226552, SR-58611-A, CP-114271, and L-755507.

Besides, examples of the therapeutic agent for diabetes include ergoset,pramlintide, leptin, and BAY-27-9955.

Examples of the therapeutic agent for cerebrovascular disorder includeNicaraven, Bencyclane fumarate, Eurnamonine, Flunarizine, Nilvadipine,Ibudilast, Argatroban, Nizofenone, Naftidrofuryl, Nicergoline,Nimodipine, Papaveroline, Alteplase, Viquidil hydrochloride, Moxisylyte,Pentoxifylline, Dihydroergotoxine mesylate, Lemildipine, Cyclandelate,Xanthinolnicotinate, Febarbamate, Cinnarizine, Memantine, Ifenprodil,Meclofenoxate hydrochloride, Ebselen, Clopidogrel, Nebracetam,Edaravone, Clinprost-DDS, Vatanidipine, Ancrod, Dipyridamole.

Examples of the therapeutic agent for spinal cord injury includeMethylprednisolone, and Dural graft matrix.

Examples of the therapeutic agent for spinal tumor include Nimustinehydrochloride.

Examples of the therapeutic agent for multiple sclerosis includeInterferon-β-1b.

Examples of the therapeutic agent for dementia including Alzheimer'sdisease include Aniracetam, Arginine pyroglutamte, Nefiractam,Nimodipine, Piracetam, Propentfylline, Vinpocetine, Indoloxazine,VitaminE, Cinepazide, Memantine, Lisuride hydrogen malate, Pramiracetam,Znclopenthixol, Protirelin, EGB-761, Acetyl-L-carnitine,Phosphatidylserine, Nebracetam, Taltireline, Cholinealphoscerate,Ipidacrine, Talsaclidine, Cerebrolysin, Rofecoxib, ST-618, T-588,Tacrine, Physostigmine-DOS, HuperzineA, Donepezil, Rivastigmine,Metrifonate and TAK-147.

Examples of the therapeutic agent for Parkinson's disease includeTalipexole, Amantadine, Pergolide, Bromocriptine, Selegiline,Mazaticolhydrochloride, Memantine, Lisuride hydrogen malate,Trihexyphenidyl, Piroheptinhydrochloride, Terguride, Ropinirole,Ganglioside-GM1, Droxidopa, Riluzole, Gabergoline, Entacapone,Rasagiline, Pramipexole, L-dopa-methylester, Tolcapone, Remacemida,Dihydroergocryptine, Carbidopa, Selegiline-DDS, Apomorphine,Apomorphine-DDS, Etilevodopa, and Levodopa.

Examples of the therapeutic agent for progressive supranuclear palsyinclude L-dopa, carbidopa, bromocriptine, pergolide, lisuride, andamitriptyline.

Examples of the therapeutic agent for Guillain-Barré syndrome includesteroid agent and TRH preparation such as protirelline.

Examples of the therapeutic agent for acute panautonomic abnormalityinclude steroid agent, L-threo-DOPS, dihydrideergotamine, and amezinium.

Examples of the therapeutic agent for olivopontocerebellar atrophyinclude TRH preparation, steroid agent, midodrine, and amezinium.

Examples of the therapeutic agent for cervicel vertebrae disorderinclude an anti-inflammatory agent.

Examples of the “drug which is administered for treating other diseasebut itself induces voiding disturbance” include an analgesic (morphine,tramadol hydrochloride), a central skeleton muscle relaxant (baclofen),a butyrophenone antipsychotic agent (haloperidol etc.), a therapeuticagent for a voiding frequency•urinary incontinence (muscarine antagonistsuch as oxybutynin hydrochloride, propiverine hydrochloride,tolterodine, darifenacin, YM-905/YM-537, temiverine (NS-21), KRP-197,and trospium; smooth muscle relaxant such as flavoxate hydrochloride;muscle relaxant such as NC-1800; Beta2 agonist such as clenbuterol;potassium channel opener such as ZD-0947, NS-8, KW-7158, and WAY-151616;PGE2 antagonist such as ONO-8711; vanilloid receptor agonist such asresiniferatoxin and capsaicin; tachykinin antagonist such as TAK-637,SR-48968 (saredutant), and SB-223412 (talnerant); delta opioid agonist),antispasmodic (scopolamine butylbromide, butropium bromide, tiquiziumbromide, timepidium bromide, propantheline bromide), a therapeutic agentfor digestive tract ulcer (Kolantyl, Methaphynin, cimetidine), atherapeutic agent for Parkinson's disease (trihexyphenidylhydrochloride, biperiden, mazaticol hydrochloride, levodopa), ananti-histamine drug (diphenhydramine, chlorophenylamine maleate,homochlorcyclizine hydrochloride), a tricyclic antidepressant(imipramine hydrochloride, amitriptyline hydrochloride, clomipraminehydrochloride, amoxapine, desipramine hydrochloride), phenothiazineantipsychotic agent (chlorpromazine, propericiazine, levomepromazine,thioridazine), a benzodiazepine tranquilizer•sleep-sedative (diazepam,chlordiazepoxide, clotiazepam, estazolam), an antiarrhythmic agent(disopyramide), a vasodilator (hydralazine hydrochloride), a cerebralperipheral circulation improving agent (pentoxifylline), abronchodilator (theophylline, ephedrine hydrochloride, methylephedrinehydrochloride), a β-adrenaline blocker (propranolol hydrochloride), colddrug (Danrich), a peripheral skeleton muscle relaxant (dantrolenesodium), and a antitubercular agent (isoniazid).

When Compound A, B, or C is used in combination with the aforementionedconcomitant use drug, a dose can be appropriately selected based on aminimum recommended clinical dose of individual drug as a standard,depending on an administration subject, an age and a weight of anadministration subject, condition, an administration time, anadministration method, a dosage form, and a combination of drugs. A doseof a particular patient is determined depending on an age, a bodyweight, general health state, a sex, a diet, an administration time, anadministration method, an excretion rate, a combination of drugs, and anextent of disease of a patient to be treated at that time, and takingthem and other factors into consideration.

Typically, an individual day dose regarding a combination of Compound A,B or C with at least one kind of a compound selected from remedies forvarious diseases or a salt thereof is in a range of about 1/50 a minimumrecommended clinical dose to a maximum recommended level regarding thecircumstances where they are administered alone.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention will be explained in detail below by way ofExamples, Preparation Examples, and Experimental Examples, but thepresent invention is not limited by them, and may be modified withoutdeparting from the scope of the present invention.

“Room temperature” in the following Reference Examples and Examplesdenotes 0 to 30° C. “%” means weight percentage unless otherwiseindicated.

Other abbreviations used in the present text indicate the followingmeans.

-   s; singlet-   d; doublet-   t: triplet-   q: quartet-   m: multiplet-   br: broad-   J: coupling constant-   Hz: Hertz-   CDCl₃: deuterochloroform-   DMSO-d₆: deuterodimethyl sulfoxide-   ¹H NMR: proton nuclear magnetic resonance (usually, a free compound    was measured in CDCl₃, and hydrochloride was measured in DMSO-d₆)-   IR: infrared absorption spectrum-   MS: Mass spectrum (usually, measured using an electron bombard    ionization method)

In the present specification and drawings, when a base and an amino acidare denoted by an abbreviation, it is based on abbreviations byIUPAC-AUB Commission Biochemical Nomenclature or conventionalabbreviations in the art, and examples are shown below. When an aminoacid can have an optical isomer, it denotes a L-amino acid unlessotherwise indicated.

-   DNA: deoxyribonucleic acid-   cDNA: complementary deoxyribonucleic acid-   A: adenine-   T: thymine-   G: guanine-   C: cytosine-   ATP: adenosine triphosphate-   EDTA: ethylenediaminetetraacetic acid

EXAMPLES Reference Example 18-(5-Chloropentanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one

Aluminum chloride (55 g, 410 mmol) was added by portions to a solutionof 1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (30.0 g) and5-chlorovaleryl chloride (26.8 ml) in 1,2-dichloroethane (70 ml) underice-cooling. After stirring at room temperature for 30 minutes, thereaction mixture was poured into ice (500 g), extracted with ethylacetate, and washed with brine. The organic layer was dried overanhydrous magnesium sulfate, the solvent was evaporated under reducedpressure, and the residue was recrystallized from ethanol-diethyl etherto give a pale yellow solid (36.5 g). Further recrystallization fromethanol-diethyl ether afforded the title compound as colorless crystals(32.4 g) having a melting point of 110–111° C.

¹H NMR (200 MHz, CDCl₃) δ 1.80–2.00 (4H, m), 2.72 (2H, t, J=7.8 Hz),2.85–3.15 (4H, m), 3.23 (2H, t, J=8.6 Hz), 3.55–3.65 (2H, m), 4.14(2H,t, J=8.6 Hz), 7.68 (1H, s), 7.72 (1H, s). elementary analysis asC₁₆H₁₈ClNO₂ calculation value: C, 65.86; H, 6.22; N, 4.80. experimentalvalue: C, 66.29; H, 6.28; N, 4.82.

Reference Example 28-(6-Bromohexanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one

Using 1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (3.00 g) and6-bromohexanoyl chloride (2,91 ml) according to the same method as thatof Reference Example 1, the title compound (3.94 g) was obtained aswhite crystals having a melting point of 97 to 98° C.

¹H NMR (200 MHz, CDCl₃) δ 1.40–1.60 (2H, m), 1.65–2.00 (4H,m), 2.72 (2H,t, J=7.8 Hz), 2.94 (2H, t, J=7.0 Hz), 3.03 (2H, t, J=7.8 Hz),3.23 (2H,t, J=8.4 Hz), 3.43 (2H, t, J=7.0 Hz), 4.14 (2H, t, J=8.4Hz), 7.68(1H,s), 7.72 (1H, s).

Reference Example 38-(5-Chloropentanoyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-one

Using 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-one (3.46 g) and5-chlorovaleryl chloride (3.4 g) according to the same method as that ofReference Example 1, the title compound (3.78 g) was obtained as paleyellow crystals having a melting point of 89 to 90° C.

¹H NMR (400 MHz, CDCl₃) δ 1.85–1.94 (4H, m), 2.01–2.07 (2H,m), 2.83 (2H,t, J=6 Hz), 2.96 (2H, t, J=7 Hz), 3.55 (2H, s), 3.60 (2H, d, J=4 Hz),3.74 (2H, d, J=6 Hz), 7.73 (2H, s). IR (KBr) νcm⁻¹: 1718, 1667, 1605,1501, 1345, 1289, 1152.

Reference Example 48-(6-bromohexanoyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-one

Using 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-one and6-bromohexanoyl chloride according to the same method as that ofReference Example 1, the title compound (5.13 g) was obtained ascolorless crystals having a melting point of 86 to 87° C.

¹H NMR (400 MHz, CDCl₃) δ 1.50–1.57 (2H, m), 1.73–1.80 (2H,m), 1.88–1.96(2H, m), 2.01–2.07 (2H, m), 2.83 (2H, t, J=6 Hz), 2.94 (2H, t, J=7 Hz),3.43 (2H, t, J=7 Hz), 3.56 (2H, s), 3.74 (2H, d, J=6 Hz), 7.73 (2H,s).IR (KBr) νcm⁻¹: 1711, 1674, 1602, 1496, 1350, 1276, 1162.

Reference Example 59-(5-Chloropentanoyl)-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-one

Using 2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-one and5-chlorovaleryl chloride according to the same method as that ofReference Example 1, the title compound (3.53 g) was obtained ascolorless crystals having a melting point of 83–84° C.

¹H NMR (400 MHz, CDCl₃) δ 1.35–2.00 (6H, m), 2.68 (2H, t, J=7.5 Hz),2.85 (2H, t, J=6 Hz), 2.93–2.98 (4H, m), 3.59 (2H, t, J=6 Hz), 3.89(2H,d, J=6 Hz), 7.63 (2H, d, J=5.3 Hz). IR (KBr) νcm⁻: 1675, 1602, 1365,1301, 1156.

Reference Example 69-(6-Bromohexanoyl)-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-one

Using 2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-one and6-bromohexanoyl chloride according to the same method as that ofReference Example 1, the title compound (3.90 g) was obtained ascolorless crystals having a melting point of 52–53° C.

¹H NMR (400 MHz, CDCl₃) δ 1.50–1.57 (2H, m), 1.73–1.80 (2H,m), 1.89–2.00(4H, m), 2.68 (2H, t, J=7 Hz), 2.85 (2H, t, J=6 Hz), 2.93–2.97(4H, m),3.43 (2H, t, J=6 Hz), 3.89 (2H, d, J=6 Hz), 7.62 (2H, d, J=5.3 Hz).IR(KBr)νcm⁻¹: 1667, 1600, 1358, 1337, 1158.

Reference Example 7 6-(5-Chloropentanoyl)-2H-1,4-benzoxazin-3(4H)-one

Using 2H-1,4-benzoxazin-3(4H)-one (10.0 g) and 5-chlorovaleryl chloride(12.5 g) according to the same method as that of Reference Example 1,the title compound (12.0 g) was obtained as colorless crystals.

¹H NMR (200 MHz, CDCl₃) δ 1.69–1.92 (4H, m), 2.97 (2H, t, J=6.8 Hz),3.59 (2H, t, J=6.1 Hz), 4.71 (2H, s), 7.03 (1H, d, J=8.4 Hz), 7.52(1H,d, J=0.9 Hz), 7.61 (1H, dd, J=8.4, 2.2 Hz), 8.52 (1H, s). elementaryanalysis as C₁₃H₁₄ClNO₃ calculation value: C, 58.32; H, 5.27; N, 5.23.experimental value: C, 58.06; H, 5.55; N, 4.96.

Reference Example 8 6-(6-Bromohexanoyl)-2H-1,4-benzoxazin-3(4H)-one

Using 2H-1,4-benzoxazin-3(4H)-one (15.0 g) and 6-bromohexanoyl chloride(2.5.8 g) according to the same method as that of Reference Example 1,the title compound (1.4.8 g) was obtained as colorless crystals.

¹H NMR (200 MHz, CDCl₃) δ 1.50–1.58 (2H, m), 1.73–1.83 (2H,m), 1.88–1.97(2H, m), 2.95 (2H, t, J=4.8 Hz), 3.44 (2H, t, J=4.5 Hz), 4.71(2H, s),7.02 (1H, d, J=5.4 Hz), 7.57 (1H, d, J=1.4 Hz), 7.61 (1H, dd, J=5.6, 1.2Hz), 9.02 (1H, s). elementary analysis as C₁₄H₁₆BrNO₃ calculation value:C, 51.55; H, 4.94; N, 4.29. experimental value: C, 52.14; H, 4.87; N,4.32. MS m/z: 327 [M+H]⁺

Reference Example 95-(5-Chloropentanoyl)-1,3-dihydro-2H-benzimidazol-2-one

Using 1,3-dihydro-2H-benzimidazol-2-one (4.00 g) and 5-chlorovalerylchloride (9.24 g) according to the same method as that of ReferenceExample 1, the title compound (4.36 g) was obtained as colorlesscrystals.

¹H NMR (300 MHz, DMSO-d₆) δ 1.76 (4H, m), 2.99–3.04 (2H, m),3.65–3.69(2H, m), 7.00 (1H, d, J=8.4 Hz), 7.48 (1H, s), 7.67 (1H, dd, J=8.2, 1.4Hz), 10.88 (1H, s), 11.04 (1H, s). MS m/z: 253 [M+H]⁺

Reference Example 105-(5-Chloropentanoyl)-1,3-dimethyl-1,3-dihydro-2H-benzimidazol-2-one

Using 1,3-dimethyl-1,3-dihydro-2H-benzimidazol-2-one (3.00 g) and5-chlorovaleryl chloride (5.74 g) according to the same method as thatof Reference Example 1, the title compound (3.67 g) was obtained ascolorless crystals.

¹H NMR (300 MHz, DMSO-d₆) δ 1.74–1.80 (4H, m), 3.06–3.11 (2H,m), 3.38(6H, d, J=3.4 Hz), 3.68–3.72 (2H, m), 7.26 (1H, d, J=8.1 Hz), 7.48(1H,d, J=1.5 Hz), 7.81 (1H, dd, J=8.3, 1.7 Hz).

Reference Example 111-(1-Acetyl-2,3-dihydro-1H-indol-5-yl)-5-chloropentan-1-one

Using 1-acetylindoline (1.60 g) and 5-chlorovaleryl chloride (1.70 g)according to the same method as that of Reference Example 1, the titlecompound (1.26 g) was obtained as colorless crystals having a meltingpoint of 90 to 91° C.

¹H NMR (400 MHz, CDCl₃) δ 1.84–1.88 (4H, m), 2.26 (3H, s), 2.97 (2H, t,J=7 Hz), 3.24 (2H, t, J=8 Hz), 3.58 (2H, t, J=6 Hz), 4.12 (2H,t, J=8Hz), 7.82 (2H, br.d, J=10 Hz), 8.23 (1H, d, J=8 Hz). IR (KBr)νcm⁻¹:1666, 1603, 1488, 1442, 1398, 1336, 1235.

Reference Example 121-(1-Acetyl-2,3-dihydro-1H-indol-5-yl)-6-bromo-1-hexanone

Using 1-acetylindoline and 6-bromohexanoyl chloride according to thesame method as that of Reference Example 1, the title compound (1.27 g)was obtained as colorless crystals having a melting point of 110 to 111°C.

¹H NMR (400 MHz, CDCl₃) δ 1.49–1.57 (2H, m), 1.72–1.79 (2H,m), 1.88–1.95(2H, m), 2.52 (3H, s), 2.94 (2H, t, J=7.5 Hz), 3.23 (2H, t, J=8 Hz),3.42 (2H, t, J=6 Hz), 4.12 (2H, t, J=8 Hz), 7.82 (2H, br.d, J=10Hz),8.23 (1H, d, J=8 Hz). IR (KBr)νcm⁻¹: 1665, 1600, 1487, 1440, 1390,1322, 1257.

Reference Example 13N-[5-(5-Chloropentanoyl)-2-methoxyphenyl]methanesulfonamide

Using N-(2-methoxyphenyl)methanesulfonamide (10.0 g) and 5-chlorovalerylchloride (7.06 ml) according to the same method as that of ReferenceExample 1, the title compound (9.15 g) was obtained as colorlesscrystals.

¹H NMR(300 MHz, CDCl₃) δ 1.80–1.95 (4H, m), 2.98 (2H, t, J=6.9 Hz), 3.00(3H, s), 3.58 (2H, t, J=6.3 Hz), 3.97 (3H, s), 6.58 (1H, s), 6.99(1H, d,J=8.4 Hz), 7.82 (1H, dd, J=8.4, 1.8 Hz), 8.11 (1H, d, J=1.8 Hz).

Reference Example 14N-[5-(6-Bromohexanoyl)-2-methoxyphenyl]methanesulfonamide

Using N-(2-methoxyphenyl)methanesulfonamide (10.0 g) and 6-bromohexanoylchloride (8.37 ml) according to the same method as that of ReferenceExample 1, the title compound (9.80 g) was obtained as colorlesscrystals.

¹H NMR(300 MHz, DMSO-d₆) δ 135–1.45 (2H, m), 1.55–1.70 (2H,m), 1.75–1.90(2H, m), 2.90–3.00 (5H, m), 3.51 (2H, t, J=6.6 Hz), 3.89 (3H,s), 7.16(1H, d, J=8.4 Hz), 7.80–7.90 (2H, m), 9.11 (1H, s).

Reference Example 15 5-Chloro-1-(1H-indol-3-yl)-1-pentanone

Using indole (1.00 g) and 5-chlorovaleryl chloride (1.68 ml) accordingto the same method as that of Reference Example 1, the title compound(1.55 g) was obtained as colorless crystals having a melting point of165 to 167° C.

¹H NMR(300 MHz, DMSO-d₆) δ 1.60–1.90 (4H, m), 2.89 (2H, t, J=6.9 Hz),3.69 (2H, t, J=6.1 Hz), 7.10–7.30 (2H, m), 7.40–7.50 (1H, m),8.10–8.25(1H, m), 8.34 (1H, d, J=3.0 Hz), 11.92 (1H, s).

Reference Example 16 6-Bromo-1-(1H-indol-3-yl)-1-hexanone

Using indole (5.00 g) and 6-bromohexanoyl chloride (9.95 ml) accordingto the same method as that of Reference Example 1, the title compound(9.65 g) was obtained as colorless crystals having a melting point of150 to 151° C.

¹H NMR(300 MHz, DMSO-d₆) δ 1.40–1.95 (6H, m), 2.86 (2H, t, J=7.4 Hz),3.54 (2H, t, J=6.8 Hz), 7.10–7.30 (2H, m), 7.40–7.50 (1H, m),8.15–8.25(1H, m), 8.34 (1H, d, J=3.2 Hz), 11.91 (1H, s).

Reference Example 17 5-Chloro-1-(2-thienyl)-1-pentanone

Using thiophene (1.00 ml) and 5-chlorovaleryl chloride (1.63 ml)according to the same method as that of Reference Example 1, the titlecompound (2.20 g) was obtained as a pale yellow solid.

¹H NMR(300 MHz, CDCl₃) δ 1.80–2.00 (4H, m), 2.96 (2H, t, J=7.2 Hz), 3.58(2H, t, J=6.3 Hz), 7.14 (1H, dd, J=5.0, 3.6 Hz), 7.64 (1H, dd, J=5.0,1.2 Hz), 7.77 (1H, dd, J=3.6, 1.2 Hz).

Reference Example 18 6-Bromo-1-(2-thienyl)-1-hexanone

Using thiophene (5 ml) and 6-bromohexanoyl chloride (10.5 ml) accordingto the same method as that of Reference Example 1, the title compound(12.8 g) was obtained as a pale red solid.

¹H NMR(200 MHz, CDCl₃) δ 1.40–2.00 (6H, m), 2.93 (2H, t, J=7.2 Hz), 3.42(2H, t, J=6.8 Hz), 7.13 (1H, dd, J=5.0, 3.6 Hz), 7.63 (1H, dd, J=5.0,1.2 Hz), 7.71 (1H, dd, J=3.6, 1.2 Hz).

Reference Example 19 tert-Butyl5-oxo-5-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)pentyl(2-phenylethyl)carbamate

A mixture of8-(5-chloropentanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(3.00 g) obtained in Reference Example 1 and 2-phenylethylamine (2.50 g)was stirred at 120° C. for 5 minutes. After cooling to room temperature,methanol (20 ml) and triethylamine (6.89 ml) were added to the reactionmixture, and a solution of di-t-butyl dicarbonate (9.00 g) in methanol(10 ml) was added dropwise, followed by stirring at room temperature for12 hours. The solvent was evaporated under reduced pressure, water wasadded to the resulting residue, and extracted with ethyl acetate. Theextract was washed with brine, and dried over anhydrous magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theresulting residue was purified by silica gel chromatography (elutingsolvent; hexane:ethyl acetate=1:1) to give the title compound as a paleyellow oil (3.00 g).

¹H NMR(200 MHz, CDCl₃) δ 1.44 (9H, s), 1.45–1.80 (4H, m), 2.71 (2H, t,J=7.8 Hz), 2.75–3.00 (4H, m), 3.01 (2H, t, J=7.8 Hz), 3.05–3.30(4H, m),3.30–3.45 (2H, m), 4.12 (2H, t, J=9.2 Hz), 7.10–7.35 (5H, m), 7.67(1H,s), 7.71 (1H, s).

Reference Example 20 tert-Butyl2-(2-methoxyphenyl)ethyl[5-oxo-5-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)pentyl]carbamate

Using8-(5-chloropentanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(800 mg) obtained in Reference Example 1 and2-(2-methoxyphenyl)ethylamine (1.24 g) according to the same method asthat of Reference Example 19, the title compound (1.16 g) was obtainedas a pale yellow oil.

¹H NMR(300 MHz,CDCl₃) δ 1.43 (9H, s), 1.45–1.75 (4H, m), 2.71 (2H, t,J=7.8 Hz), 2.75–3.00(4H, m), 3.01 (2H, t, J=7.8 Hz), 3.05–3.30 (4H, m),3.30–3.40 (2H, m), 3.82(3H, s), 4.12 (2H, t, J=8.4 Hz), 6.80–6.90 (2H,m), 7.05–7.25 (2H, m), 7.67(1H, s), 7.72 (1H, s).

Reference Example 21 tert-Butyl2-(3-methoxyphenyl)ethyl[5-oxo-5-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)pentyl]carbamate

Using8-(5-chloropentanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(2.00 g) obtained in Reference Example 1 and2-(3-methoxyphenyl)ethylamine (3.11 g) according to the same method asthat of Reference Example 19, the title compound (3.02 g) was obtainedas a pale yellow oil.

¹H NMR(200 MHz, CDCl₃) δ 1.45 (9H, s), 1.50–1.80 (4H, m),2.71 (2H, t,J=7.8 Hz), 2.75–3.00 (4H, m), 3.02 (2H, t, J=7.8 Hz), 3.10–3.25(4H, m),3.30–3.45 (2H, m), 3.79 (3H, s), 4.13 (2H, t, J=8.2 Hz), 6.65–6.85(3H,m), 7.20 (1H, t, J=7.8 Hz), 7.67 (1H, s), 7.72 (1H, s).

Reference Example 22 tert-Butyl2-(3,4-dimethoxyphenyl)ethyl[5-oxo-5-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)pentyl]carbamate

Using8-(5-chloropentanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(500 mg) obtained in Reference Example 1 and2-(3,4-dimethoxyphenyl)ethylamine (930 mg) according to the same methodas that of Reference Example 19, the title compound (408 mg) wasobtained as a pale yellow oil.

¹H NMR(200 MHz, CDCl₃) δ 1.45 (9H, s), 1.45–1.80 (4H, m), 2.71 (2H, t,J=7.8 Hz), 2.75–3.00(4H, m), 3.02 (2H, t, J=7.8 Hz), 3.05–3.30 (4H, m),3.30–3.40 (2H, m), 3.86(3H, s), 3.87 (3H, s), 4.13 (2H, t, J=8.4 Hz),6.65–6.85 (3H, m), 7.67 (1H,s), 7.71 (1H, s).

Reference Example 23 tert-Butyl2-(2-chrolophenyl)ethyl[5-oxo-5-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)pentyl]carbamate

Using8-(5-chloropentanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(1.00 g) obtained in Reference Example 1 and2-(2-chlorophenyl)ethylamine (1.60 g) according to the same method asthat of Reference Example 19, the title compound (1.50 g) was obtainedas a pale yellow oil.

¹H NMR(200 MHz, CDCl₃) δ 1.41 (9H, s), 1.50–1.80 (4H, m),2.71 (2H, t,J=7.8 Hz), 2.80–3.35 (10H, m), 3.41 (2H, t, J=7.8 Hz), 4.13 (2H,t, J=8.2Hz), 7.00–7.40 (4H, m), 7.67 (1H, s), 7.72 (1H, s).

Reference Example 24 tert-Butyl2-(3-fluorophenyl)ethyl[5-oxo-5-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)pentyl]carbamate

Using8-(5-chloropentanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(1.00 g) obtained in Reference Example 1 and2-(3-fluorophenyl)ethylamine (1.43 g) according to the same method asthat of Reference Example 19, the title compound (1.40 g) was obtainedas a pale yellow oil.

¹H NMR(200 MHz, CDCl₃) δ 1.44 (9H, s), 1.50–1.80 (4H, m), 2.71 (2H, t,J=7.8 Hz), 2.75–3.30 (10H, m), 3.39 (2H, t, J=7.8 Hz), 4.13 (2H,t, J=8.2Hz), 6.80–7.05 (3H, m), 7.15–7.30 (1H, m), 7.68 (1H, s), 7.72 (1H,s).

Reference Example 25 tert-Butyl2-[3-(aminosulfonyl)-4-methoxyphenyl]ethyl[5-oxo-5-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)pentyl]carbamate

Using8-(5-chloropentanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(800 mg) obtained in Reference Example 1 and2-[3-(aminosulfonyl)-4-methoxyphenyl]ethylamine (1.89 g) according tothe same method as that of Reference Example 19, the title compound (605mg) was obtained as a pale yellow oil.

¹H NMR(200 MHz, CDCl₃) δ 1.40–1.80 (4H, m), 1.44 (9H, s), 2.70 (2H, t,J=7.6 Hz), 2.80 (2H,t, J=7.6 Hz), 2.92 (2H, t, J=7.4 Hz), 3.02 (2H, t,J=7.6 Hz), 3.10–3.25 (2H,m), 3.22 (2H, t, J=8.6 Hz), 3.35 (2H, t, J=7.6Hz), 3.99 (3H, s), 4.10 (2H,t, J=8.8 Hz), 5.30 (2H, s), 6.98 (1H, d,J=8.4 Hz), 7.20–7.45 (1H, m),7.60–7.75 (3H, m).

Reference Example 26 tert-Butyl2-(2-methoxyphenyl)-1-methylethyl[5-oxo-5-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)pentyl]carbamate

Using8-(5-chloropentanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(500 mg) obtained in Reference Example 1 and2-(2-methoxyphenyl)-1-methylethylamine (848 mg) according to the samemethod as that of Reference Example 19, the title compound (641 mg) wasobtained as a pale yellow oil.

¹H NMR(200 MHz, CDCl₃) δ 1.19 (3H, d, J=7.0 Hz), 1.30–2.00(9H, m), 1.37(9H, s), 2.71 (2H, t, J=7.6 Hz), 2.80–3.10 (6H, m), 3.22 (2H, t,J=8.4Hz), 3.82 (3H, s), 4.13 (2H, t, J=8.8 Hz), 6.75–7.20 (2H, m), 7.67(1H,s), 7.71 (1H, s).

Reference Example 27 tert-Butyl6-oxo-6-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)hexyl(2-phenylethyl)carbamate

Using8-(6-bromohexanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(500 mg) obtained in Reference Example 2 and 2-phenylethylamine (0.538ml) according to the same method as that of Reference Example 19, thetitle compound (450 mg) was obtained as a pale yellow oil.

¹H NMR(300 MHz, CDCl₃) δ 1.25–1.60 (4H, m), 1.44 (9H, s),1.65–1.80 (2H,m), 2.71 (2H, t, J=7.5 Hz), 2.75–2.90 (2H, m), 2.90 (2H, t, J=7.5 Hz),3.01 (2H, t, J=7.5 Hz), 3.05–3.45 (4H, m), 3.22 (2H, t, J=8.4 Hz),4.12(2H, t, J=8.4 Hz), 7.10–7.35 (5H, m), 7.67 (1H, s), 7.71 (1H, s).

Reference Example 28 tert-Butyl2-(2-methoxyphenyl)ethyl[6-oxo-6-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)hexyl]carbamate

Using8-(6-bromohexanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(1.50 g) obtained in Reference Example 2 and2-(2-methoxyphenyl)ethylamine (1.94 g) according to the same method asthat of Reference Example 19, the title compound (1.51 g) was obtainedas a pale yellow oil.

¹H NMR(300 MHz, CDCl₃) δ 1.25–1.60 (4H, m), 1.43 (9H, s),1.65–1.80 (2H,m), 2.71 (2H, t, J=7.5 Hz), 2.75–2.90 (2H, m), 2.90 (2H, t, J=7.5 Hz),3.01 (2H, t, J=7.5 Hz), 3.05–3.45 (6H, m), 3.82 (3H, s), 4.12 (2H,t,J=8.4 Hz), 6.80–6.90 (2H, m), 7.00–7.20 (2H, m), 7.67 (1H, s), 7.71(1H, s).

Reference Example 29 tert-Butyl2-(3-methoxyphenyl)ethyl[6-oxo-6-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)hexyl]carbamate

Using8-(6-bromohexanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(500 mg) obtained in Reference Example 2 and2-(3-methoxyphenyl)ethylamine (650 mg) according to the same method asthat of Reference Example 19, the title compound (562 mg) was obtainedas a pale yellow oil.

¹H NMR(300 MHz, CDCl₃) δ 1.25–1.60 (4H, m), 1.45 (9H, s), 1.74 (2H, tt,J=7.5, 7.5 Hz), 2.71(2H, t, J=7.8 Hz), 2.75–2.85 (2H, m), 2.90 (2H, t,J=7.5 Hz), 3.01 (2H, t, J=7.8 Hz), 3.05–3.45 (4H, m), 3.22 (2H, t, J=8.4Hz), 3.79 (3H, s), 4.12 (2H,t, J=8.4 Hz), 6.70–6.85 (3H, m), 7.20 (1H,t, J=7.8 Hz), 7.67 (1H, s), 7.71(1H, s).

Reference Example 30 tert-Butyl2-(4-methoxyphenyl)ethyl[6-oxo-6-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)hexyl]carbamate

Using8-(6-bromohexanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(700 mg) obtained in Reference Example 2 and2-(4-methoxyphenyl)ethylamine (907 mg) according to the same method asthat of Reference Example 19, the title compound (900 mg) was obtainedas a pale yellow oil.

¹H NMR(300 MHz, CDCl₃) δ 1.25–1.55 (4H, m), 1.41 (9H, s),1.60–1.75 (2H,m), 2.60–2.75 (4H, m), 2.85 (2H, t, J=7.5 Hz), 2.97 (2H, t, J=7.8 Hz),3.00–3.35 (4H, m), 3.17 (2H, t, J=8.4 Hz), 3.74 (3H, s), 4.08 (2H,t,J=8.4 Hz), 6.75–6.80 (2H, m), 7.00–7.10 (2H, m), 7.63 (1H, s), 7.67(1H, s).

Reference Example 31 tert-Butyl2-(chlorophenyl)ethyl[6-oxo-6-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)hexyl]carbamate

Using8-(6-bromohexanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(500 mg) obtained in Reference Example 2 and 2-(chlorophenyl)ethylamine(430 mg) according to the same method as that of Reference Example 19,the title compound (540 mg) was obtained as a pale yellow oil.

¹H NMR(300 MHz, CDCl₃) δ 1.25–1.60 (4H, m), 1.41 (9H, s),1.65–1.80 (2H,m), 2.71 (2H, t, J=7.5 Hz), 2.85–3.30 (4H, m), 2.89 (2H, t, J=7.5 Hz),3.01 (2H, t, J=7.8 Hz), 3.22 (2H, t, J=8.4 Hz), 3.39 (2H, t, J=7.5 Hz),4.12 (2H, t, J=8.4 Hz), 7.10–7.35 (4H, m), 7.67 (1H, s), 7.71 (1H, s).

Reference Example 32 tert-Butyl2-(3-fluorophenyl)ethyl[6-oxo-6-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)hexyl]carbamate

Using8-(6-bromohexanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(500 mg) obtained in Reference Example 2 and2-(3-fluorophenyl)ethylamine (600 mg) according to the same method asthat of Reference Example 19, the title compound (613 mg) was obtainedas a colorless oil.

¹H NMR(300 MHz, CDCl₃) δ 1.25–1.60 (4H, m), 1.44 (9H, s),1.74 (2H, tt,J=7.5, 7.5 Hz), 2.71 (2H, t, J=7.5 Hz), 2.75–2.90 (2H, m), 2.90(2H, t,J=7.5 Hz), 3.02 (2H, t, J=7.8 Hz), 3.05–3.45 (2H, m), 3.22 (2H, t, J=8.4Hz), 3.37 (2H, t, J=7.5 Hz), 4.13 (2H, t, J=8.4 Hz), 6.80–7.00 (3H,m),7.20–7.30 (1H, m), 7.67 (1H, s), 7.71 (1H, s).

Reference Example 33 tert-Butyl2-(2-methoxyphenyl)-1-methylethyl[6-oxo-6-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)hexyl]carbamate

Using8-(6-bromohexanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(600 mg) obtained in Reference Example 2 and2-(2-methoxyphenyl)-1-methyl ethylamine (850 mg) according to the samemethod as that of Reference Example 19, the title compound (467 mg) wasobtained as a pale yellow oil.

¹H NMR(300 MHz, CDCl₃) δ 1.18 (3H, d, J=6.9 Hz), 1.25–1.90(6H, m), 1.36(9H, s), 2.71 (2H, t, J=7.5 Hz), 2.75–3.20 (5H, m), 2.88 (2H, t,J=7.5Hz), 3.02 (2H, t, J=7.8 Hz), 3.22 (2H, t, J=8.4 Hz), 3.82 (3H, s),4.13(2H, t, J=8.4 Hz), 6.80–7.25 (4H, m), 7.67 (1H, s), 7.72 (1H, s).

Reference Example 34 tert-Butyl5-oxo-5-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)pentyl(3-phenylpropyl)carmamate

Using8-(5-chloropentanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(500 mg) obtained in Reference Example 1 and 3-phenyl-1-propylamine (694mg) according to the same method as that of Reference Example 19, thetitle compound (660 mg) was obtained as a pale yellow oil.

¹H NMR(200 MHz, CDCl₃) δ 1.20–2.00 (6H, m), 1.43 (9H, s), 2.60(2H, t,J=7.8 Hz), 2.71 (2H, t, J=7.5 Hz), 2.93 (2H, t, J=7.5 Hz), 3.01 (2H,t,J=7.8 Hz), 3.10–3.40 (6H, m), 4.13 (2H, t, J=8.4 Hz), 7.10–7.35 (5H,m),7.67 (1H, s), 7.71 (1H, s).

Reference Example 35 tert-Butyl6-oxo-6-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)hexyl(3-phenylpropyl)carbamate

Using8-(6-bromohexanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(700 mg) obtained in Reference Example 2 and 3-phenyl-1-propylamine (811mg) according to the same method as that of Reference Example 19, thetitle compound (906 mg) was obtained as a colorless oil.

¹H NMR (300 MHz, CDCl₃) δ 1.20–1.60 (4H, m), 1.44 (9H, s),1.74 (2H, tt,J=7.5, 7.5 Hz), 1.84 (2H, tt, J=7.5, 7.5 Hz), 2.59 (2H, t, J=7.8 Hz),2.71 (2H, t, J=7.5 Hz), 2.90 (2H, t, J=7.5 Hz), 3.02 (2H, t, J=7.8 Hz),3.10–3.30 (6H, m), 4.12 (2H, t, J=8.4 Hz), 7.10–7.30 (5H, m), 7.67(1H,s), 7.72 (1H, s).

Reference Example 36 tert-Butyl2-(2-methoxyphenyl)ethyl[5-oxo-5-(2-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)pentyl]carbamate

Using8-(5-chloropentanoyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-one(293 mg) obtained in Reference Example 3 and2-(2-methoxyphenyl)ethylamine (378 mg) according to the same method asthat of Reference Example 19, the title compound (86 mg) was obtained asa pale yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 1.43 (9H, s), 1.51–1.76 (4H, m),2.00–2.07 (2H,m), 2.81 (4H, t, J=6 Hz), 2.88–2.96 (2H, m), 3.10–3.25 (2H, m),3.32–3.41(2H, m), 3.54 (2H, s), 3.74 (2H, t, J=6 Hz), 3.82 (3H, s), 6.83–6.89(2H,m), 7.09–7.21 (2H, m), 7.73 (2H, s).

Reference Example 37 tert-Butyl2-(2-chlorophenyl)ethyl[5-oxo-5-(2-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)pentyl]carbamate

Using8-(5-chloropentanoyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-oneobtained in Reference Example 3 and 2-(2-chlorophenyl)ethylamineaccording to the same method as that of Reference Example 19, the titlecompound (147 mg) was obtained as a pale yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 1.41 (9H, s), 1.51–1.76 (4H, m), 2.00–2.06(2H, m), 2.82 (2H, t, J=6 Hz), 2.87–3.00 (4H, m), 3.10–3.26 (2H, m),3.41 (2H, t, J=7 Hz), 3.54 (2H, s), 3.74 (2H, t, J=6 Hz), 7.13–7.24 (3H,m), 7.33 (1H, d, J=7.2 Hz), 7.73 (2H, s).

Reference Example 38 tert-Butyl5-oxo-5-(3-oxo-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-9-yl)pentyl(2-phenylethyl)carbamate

Using 9-(5-chloropentanoyl)-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-one obtained in Reference Example 5 and2-phenylethylamine according to the same method as that of ReferenceExample 19, the title compound (320 mg) was obtained as a pale yellowoil.

¹H NMR (400 MHz, CDCl₃) δ 1.44 (9H, s), 1.51–1.75 (4H, m),1.93–1.99 (2H,m), 2.67 (2H, t, J=6 Hz), 2.82–2.85 (4H, m), 2.92–2.95 (4H, m),3.12–3.24(2H, m), 3.32–3.42 (2H, m), 3.89 (2H, t, J=6 Hz), 7.18–7.30 (5H, m),7.61(2H, d, J=5 Hz).

Reference Example 39 tert-Butyl2-(2-methoxyphenyl)ethyl[5-oxo-5-(3-oxo-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-9-yl)pentyl]carbamate

Using9-(5-chloropentanoyl)-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-oneobtained in Reference Example 5 and 2-(2-methoxyphenyl)ethylamineaccording to the same method as that of Reference Example 19, the titlecompound (414 mg) was obtained as a pale yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 1.43 (9H, s), 1.51–1.76 (4H, m),1.93–1.99 (2H,m), 2.67 (2H, t, J=6 Hz), 2.82–2.85 (4H, m), 2.91–2.95 (4H, m),3.13–3.25(2H, m), 3.31–3.42 (2H, m), 3.82 (3H, s), 3.89 (2H, t, J=6 Hz),6.83–6.89(2H, m), 7.07–7.21 (2H, m), 7.61 (2H, d, J=5 Hz).

Reference Example 40 tert-Butyl2-(2-chlorophenyl)ethyl[5-oxo-5-(3-oxo-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-9-yl)pentyl]carbamate

Using9-(5-chloropentanoyl)-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-oneobtained in Reference Example 5 and 2-(2-chlorophenyl)ethylamineaccording to the same method as that of Reference Example 19, the titlecompound (385 mg) was obtained as a pale, yellow oil.

¹H NMR (400 MHz, CDCl₃), δ 1.41 (9H, s), 1.51–1.76, (4H, m),1.93–1.99(2H, m), 2.67 (2H, t, J=6 Hz), 2.84 (2H, t, J=6 Hz), 2.94 (6H, t, J=6.8Hz), 3.12–3.26 (2H, m), 3.41 (2H, t, J=7 Hz), 3.89 (2H, t, J=6Hz),7.13–7.19 (3H, m), 7.33 (1H, d, J=7.2 Hz), 7.62 (2H, d, J=5 Hz).

Reference Example 41 tert-Butyl5-oxo-5-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)pentyl(2-phenylethyl)carbamate

Using 6-(5-chloropentanoyl)-2H-1,4-benzoxazin-3(4H)-one obtained inReference Example 7 and 2-phenylethylamine according to the same methodas that of Reference Example 19, the title compound was obtained as acolorless oil.

¹H NMR (300 MHz, CDCl₃) δ 1.44 (9H, m), 1.58 (2H, m),1.65–1.75 (2H, m),2.81 (2H, m), 2.90–2.94 (2H, m), 3.15–3.22 (2H, m), 3.37 (2H, m), 4.69(2H, s), 6.99 (1H, d, J=8.4 Hz), 7.16–7.30 (5H, m), 7.58–7.61(2H, m),9.36 (1H, s).

Reference Example 42 tert-Butyl2-(2-ethoxyphenyl)ethyl[5-oxo-5-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)pentyl]carbamate

Using 6-(5-chloropentanoyl)-2H-1,4-benzoxazin-3(4H)-one obtained inReference Example 7 and 2-(2-ethoxyphenyl)ethylamine according to thesame method as that of Reference Example 19, the title compound wasobtained as a colorless oil.

¹H NMR (300 MHz, CDCl₃) δ 1.42 (3H, t, J=6.4 Hz), 1.44 (9H,s), 1.60–1.73(4H, m), 2.83–2.94 (4H, m), 3.18–3.36 (4H, m), 3.99–4.06 (2H, m),4.68(2H, s), 6.80–6.87 (2H, m), 6.96–6.99 (1H, d, J=6.6 Hz), 7.07–7.18 (2H,m), 7.58–7.63 (2H, m), 9.67 (1H, s).

Reference Example 43 tert-Butyl2-(2-fluorophenyl)ethyl[5-oxo-5-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)pentyl]carbamate

Using 6-(5-chloropentanoyl)-2H-1,4-benzoxazin-3(4H)-one obtained inReference Example 7 and 2-(2-fluorophenyl)ethylamine according to thesame method as that of Reference Example 19, the title compound wasobtained as a colorless oil.

¹H NMR (300 MHz, CDCl₃) δ 1.42 (9H, m), 1.52–1.78 (4H, m),2.82–2.96 (4H,m), 3.25 (2H, m), 3.36–3.43 (2H, m), 4.69 (2H, s), 6.96–7.08(3H, m),7.14–7.23 (2H, m), 7.58–7.63 (2H, m), 9.16 (1H, s).

Reference Example 44 tert-Butyl2-(2-chlorophenyl)ethyl[5-oxo-5-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)pentyl]carbamate

Using 6-(5-chloropentanoyl)-2H-1,4-benzoxazin-3(4H)-one obtained inReference Example 7 and 2-(2-chlorophenyl)ethylamine according to thesame method as that of Reference Example 19, the title compound wasobtained as a colorless oil.

¹H NMR (200 MHz, CDCl₃) δ 1.42 (9H, m), 1.67 (4H, m), 2.92 (4H, m), 3.25(2H, m), 3.37–3.45 (2H, m), 4.69 (2H, s), 6.99 (1H, d, J=8.8 Hz), 7.17(3H, m), 7.30–7.34 (1H, m), 7.61–7.62 (2H, m), 9.56 (1H, s).

Reference Example 45 tert-Butyl2-(3-methoxyphenyl)ethyl[5-oxo-5-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)pentyl]carbamate

Using 6-(5-chloropentanoyl)-2H-1,4-benzoxazin-3(4H)-one obtained inReference Example 7 and 2-(3-methoxyphenyl)ethylamine according to thesame method as that of Reference Example 19, the title compound wasobtained as a colorless oil.

¹H NMR (200 MHz, CDCl₃) δ 1.45 (9H, m), 1.55–1.77 (4H, m), 2.75–2.82(2H,m), 2.88–2.95 (2H, m), 3.22 (2H, m), 3.37 (2H, m), 3.79 (3H, s), 4.69(2H, s), 6.73–6.78 (3H, m), 6.99 (1H, d, J=8.8 Hz), 7.16–7.23 (1H, m),7.58–7.62(2H, m), 9.46 (1H, s).

Reference Example 46 tert-Butyl2-(3-ethoxyphenyl)ethyl[5-oxo-5-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)pentyl]carbamate

Using 6-(5-chloropentanoyl)-2H-1,4-benzoxazin-3(4H)-one obtained inReference Example 7 and 2-(3-ethoxyphenyl)ethylamine according to thesame method as that of Reference Example 19, the title compound wasobtained as a colorless oil.

¹H NMR (200 MHz, CDCl₃) δ 1.40 (3H, t, J=7.0 Hz), 1.45 (9H,s), 1.55–1.77(4H, m), 2.74–2.81 (2H, m), 2.88–2.95 (2H, m), 3.21 (2H, m), 3.36(2H,m), 4.01 (2H, q, J=7 Hz), 4.69 (2H, s), 6.72–6.76 (3H, m), 6.99 (1H, d,J=8.8 Hz), 7.14–7.22 (1H, m), 7.58–7.62 (2H, m), 9.43 (1H, s).

Reference Example 47 tert-Butyl5-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-5-oxopentyl[2-(2-methoxyphenyl)ethyl]carbamate

Using 1-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-5-chloropentan-1-one (280mg) obtained in Reference Example 11 and 2-(2-methoxyphenyl)ethylamine(378 mg) according to the same method as that of Reference Example 19,the title compound (170 mg) was obtained as a pale yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 1.43 (9H, s), 1.51–1.72 (4H, m),2.22 (3H, s),2.75–2.88 (2H, m), 2.90–2.95 (2H, m), 3.08–3.22 (4H, m), 3.32–3.41 (2H,m), 3.81 (3H, s), 4.07, (2H, t, J=7 Hz), 6.81–6.87 (2H, m), 7.08–7.19(2H, m), 7.77–7.81 (2H, m), 8.21 (1H, d, J=8.5 Hz).

Reference Example 48 tert-Butyl5-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-5-oxopentyl(2-phenylethyl)carbamate

Using 1-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-5-chloropentan-1-one (560mg) obtained in Reference Example 11 and 2-phenylethylamine (606 mg)according to the same method as that of Reference Example 19, the titlecompound (290 mg) was obtained as a pale yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 1.44(9H, s), 1.51–1.74(4H, m), 2.25(3H, s),2.75–2.88(2H, m), 2.89–2.96(2H, m), 3.05–3.27(4H, m), 3.30–3.43 (2H, m),4.11 (2H, t, J=7.3 Hz), 7.15–7.30 (5H, m), 7.79–7.83 (2H, m), 8.22 (1H,d, J=8.5 Hz).

Reference Example 49 tert-Butyl5-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-5-oxopentyl[2-(2-chlorophenyl)ethyl]carbamate

Using 1-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-5-chloropentan-1-oneobtained in Reference Example 11 and 2-(2-chlorophenyl)ethylamineaccording to the same method as that of Reference Example 19, the titlecompound was obtained as a pale yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 1.41 (9H, s), 1.51–1.76 (4H, m), 2.25 (3H, s),2.94 (4H, br.s), 3.12 (2H, br.s), 3.22 (2H, t, J=7.6 Hz), 3.41 (2H, t,J=7 Hz), 4.11 (2H, t, J=7.3 Hz), 7.17 (3H, br.s), 7.33 (1H, d, J=7.2Hz), 7.79–7.83 (2H, m), 8.22 (1H, d, J=8.5 Hz).

Reference Example 50 tert-Butyl5-(2,3-dihydro-1H-indol-5-yl)-5-oxopentyl[2-(2-methoxyphenyl)ethyl]carbamate

A solution of potassium hydroxide (0.22 g) in methanol (4 ml) was addedat room temperature to tert-butyl5-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-5-oxopentyl[2-(2-methoxyphenyl)ethyl]carbamate(1.00 g) obtained in Reference Example 47, and heated at reflux for 2hours with stirring. The solvent was evaporated under reduced pressure,water was added to the resulting residue, and extracted with ethylacetate. The organic layer was washed with brine, dried over anhydrousmagnesium sulfate, and the solvent was evaporated under reducedpressure. The resulting residue was purified by silica gelchromatography (eluting solvent; hexane: ethyl acetate=1:1) to give thetitle compound as a pale yellow oil (700 mg).

¹H NMR (400 MHz, CDCl₃) δ 1.43 (9H, s), 1.51–1.72 (4H, m), 2.78–2.88(4H, m), 3.06 (2H, t, J=8.5 Hz), 3.08–3.24 (2H, m), 3.32–3.39 (2H, m),3.65 (2H, t, J=8.5 Hz), 3.81 (3H, s), 4.26 (1H, br.s), 6.52 (1H, d, J=8Hz), 6.82–6.88 (2H, m), 7.08–7.20 (2H, m), 7.69 (1H, d. J=8 Hz), 7.72(1H, s).

Reference Example 51 tert-Butyl5-(2,3-dihydro-1-methyl-1H-indol-5-yl)-5-oxopentyl[2-(2-methoxyphenyl)ethyl]carbamate

Potassium carbonate (166 mg) and methyl iodide (170 mg) were added to asolution of tert-butyl.5-(2,3-dihydro-1H-indol-5-yl)-5-oxopentyl[2-(2-methoxyphenyl)ethyl]carbamate(362 mg) obtained in Reference Example 50 in dimethylformamide (2 ml),and the mixture was stirred at 60 to 70° C. for 5 hours. The solvent wasevaporated under reduced pressure, water was added to the resultingresidue, and extracted with ethyl acetate. The organic layer was washedwith brine, dried over anhydrous magnesium sulfate, and the solvent wasevaporated under reduced pressure. The resulting residue was purified bysilica gel chromatography (eluting solvent; hexane:ethyl acetate=1:1) togive the title compound as a pale yellow oil (125 mg).

¹H NMR (400 MHz, CDCl₃) δ 1.43 (9H, s), 1.51–1.70 (4H, m), 2.78–2.88(4H, m), 2.84 (3H, s), 3.00 (2H, t, J=8.5 Hz), 3.08–3.24 (2H, m),3.31–3.40 (2H, m), 3.48 (2H, t, J=8.5 Hz), 3.81 (3H, s), 6.34 (1H, d,J=8 Hz), 6.82–6.88 (2H, m), 7.08–7.20 (2H, m), 7.67 (1H, s), 7.76 (1H,d, J=8 Hz).

Reference Example 52 tert-Butyl5-(1-ethyl-2,3-dihydro-1H-indol-5-yl)-5-oxopentyl[2-(2-methoxyphenyl)ethyl]carbamate

Using tert-butyl5-(2,3-dihydro-1H-indol-5-yl)-5-oxopentyl[2-(2-methoxyphenyl)ethyl]carbamateobtained in Reference Example 50 and ethyl iodide according to the samemethod as that of Reference Example 50, the title compound was obtainedas a pale yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 1.18 (3H, t, J=7.4 Hz), 1.43 (9H, s),1.51–1.72(4H, m), 2.78–2.88 (4H, m), 3.00 (2H, t, J=8.5 Hz), 3.08–3.23(2H, m), 3.25 (2H, q, J=7.4 Hz), 3.31–3.41 (2H, m), 3.52 (2H, t, J=8.5Hz), 3.81 (3H, s), 6.33 (1H, d, J=8 Hz), 6.82–6.88 (2H, m), 7.08–7.20(2H, m), 7.67 (1H, s), 7.74 (1H, d, J=8 Hz).

Reference Example 53 tert-Butyl5-[1-(3-hydroxypropyl)-2,3-dihydro-1H-indol-5-yl]-5-oxopentyl[2-(2-methoxyphenyl)ethyl]carbamate

Using tert-butyl5-(2,3-dihydro-1H-indol-5-yl)-5-oxopentyl[2-(2-methoxyphenyl)ethyl]carbamateobtained in Reference Example 50 and 3-bromo-1-propanol according to thesame method as that of Reference Example 50, the title compound wasobtained as a pale yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 1.43 (9H, s), 1.51–1.70 (4H, m), 1.75(1H,br.s), 1.85 (2H, t, J=6.7 Hz), 2.78–2.88 (4H, m), 3.01(2H, t, J=8.5 Hz),3.08–3.24 (2H, m), 3.30–3.40 (2H, m), 3.32(2H, t, J=6.7 Hz), 3.54 (2H,t, J=8.5 Hz), 3.76(2H, t, J=7.6 Hz), 3.82 (3H, s), 6.39 (1H, d, J=8 Hz),6.82–6.88 (2H, m), 7.08–7.20 (2H, m), 7.67 (1H, s), 7.73 (1H, d, J=8Hz).

Reference Example 54 Ethyl[5-(5-[(tert-butoxycarbonyl)[2-(2-methoxyphenyl)ethyl]amino]pentanoyl)-2,3-dihydro-1H-indol-1-yl]acetate

Using tert-butyl5-(2,3-dihydro-1H-indol-5-yl)-5-oxopentyl[2-(2-methoxyphenyl)ethyl]carbamateobtained in Reference Example 50 and ethyl bromoacetate according to thesame method as that of Reference Example 50, the title compound wasobtained as a pale yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 1.27 (3H, t, J=7 Hz), 1.43 (9H, s), 1.51–1.73(4H, m), 2.75–2.88 (4H, m), 3.08 (2H, t, J=8.5 Hz), 3.15–3.23(2H, m),3.30–3.40(2H, m), 3.67 (2H, t, J=8.5 Hz), 3.81(3H, s), 3.96 (2H, s),4.20 (2H, q, J=7 Hz), 6.29 (1H, d, J=8 Hz), 6.82–6.88(2H, m), 7.08–7.20(2H, m), 7.70 (1H, s), 7.73 (1H, d, J=8 Hz).

Reference Example 55 tert-Butyl5-[1-[(ethylamino)carbonyl]-2,3-dihydro-1H-indol-5-yl]-5-oxopentyl[2-(2-methoxyphenyl)ethyl]carbamate

Ethyl isocyanate (85 mg) was added to a solution of tert-butyl5-(2,3-dihydro-1H-indol-5-yl)-5-oxopentyl[2-(2-methoxyphenyl)ethyl]carbamate(362 mg) obtained in Reference Example 50 in tetrahydrofuran (2 ml), andthe mixture was stirred at 60° C. for 2 hours. The solvent wasevaporated under reduced pressure, water was added to the resultingresidue, and extracted with ethyl acetate. The organic layer was washedwith brine, dried over anhydrous magnesium sulfate, and the solvent wasevaporated under reduced pressure. The resulting residue was-purified bysilica gel chromatography (eluting solvent; hexane:ethyl acetate=1:1) togive the title compound as a pale yellow oil (254 mg).

¹H NMR (400 MHz, CD₃OD) δ 1.22 (3H, t, J=7 Hz), 1.43 (9H, s),1.51–1.73(4H, m), 2.76–2.95(4H, m), 3.07–3.23(4H, m), 3.30–3.42(4H, m),3.82(3H, s), 3.94(2H, t, J=8 Hz), 4.70(1H, br.s), 6.82–6.88(2H, m),7.08–7.20(2H, m), 7.75(1H, s), 7.80(1H, d, J=8.5 Hz), 7.96(1H, d, J=8.5Hz).

Reference Example 56 tert-Butyl2-(3-fluorophenyl)ethyl[5-oxo-5-(3-oxo-3,4-dihydro-2H-1,4-benzooxazin-6-yl)pentyl]carbamate

Using 6-(5-chloropentanoyl)-2H-1,4-benzooxazin-3(4H)-one obtained inReference Example 7 and 2-(3-fluorophenyl)ethylamine according to thesame method as that of Reference Example 19, the title compound wasobtained as a colorless oil.

¹H NMR (200 MHz, CDCl₃) δ 1.44(9H, s), 1.52–1.76(4H, m), 2.81(2H, m),2.91–2.95(2H, m), 3.14–3.23(2H, m), 3.38(2H, m), 4.69(2H, s),6.87–7.01(4H, m), 7.20–7.25(1H, m), 7.59–7.61(2H, m), 9.40(1H, s).

Reference Example 57 tert-Butyl2-(3-chlorophenyl)ethyl[5-oxo-5-(3-oxo-3,4-dihydro-2H-1,4-benzooxazin-6-yl)pentyl]carbamate

Using 6-(5-chloropentanoyl)-2H-1,4-benzooxazin-3(4H)-one obtained inReference Example 7 and 2-(3-chlorophenyl)ethylamine according to thesame method as that of Reference Example 19, the title compound wasobtained as a colorless oil.

¹H NMR (200 MHz, CDCl₃) δ 1.44(9H, s), 1.58(2H, m), 1.68–1.73(2H, m),2.79(2H, m), 2.90–2.95(2H, m), 3.14–3.23(2H, m), 3.37(2H, m), 4.69(2H,s), 6.98–7.05(2H, m), 7.17–7.21(3H, m), 7.59–7.61(2H, m), 9.46(1H, s).

Reference Example 58 tert-Butyl5-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-5-oxopentyl(2-phenylethyl)carbamate

Using5-(5-chloropentanoyl)-1,3-dimethyl-1,3-dihydro-2H-benzimidazol-2-oneobtained in Reference Example 10 and 2-phenylethylamine according to thesame method as that of Reference Example 19, the title compound wasobtained as a colorless oil.

¹H NMR (300 MHz, CDCl₃) δ 1.44 (9H, s), 1.75–1.59(4H, m), 2.79–2.81(2H,m), 3.03–2.99(2H, m), 3.22–3.18(2H, m), 3.39–3.35(2H, m), 3.46(3H, s),3.47(3H, s), 6.99(1H, d, J=8.1 Hz), 7.31–7.16(5H, m), 7.63(1H, d, J=1.2Hz), 7.78(1H, d, J=8.4 Hz).

Reference Example 59 tert-Butyl5-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-5-oxopentyl[2-(2-methoxyphenyl)ethyl]carbamate

Using5-(5-chloropentanoyl)-1,3-dimethyl-1,3-dihydro-2H-benzimidazol-2-oneobtained in Reference Example 10 and 2-(2-methoxyphenyl)ethylamineaccording to the same method as that of Reference Example 19, the titlecompound was obtained as a colorless oil.

¹H NMR (300 MHz, CDCl₃) δ 1.43(9H, s), 1.73–1.64(4H, m), 2.84–2.80(2H,m), 3.03–2.99(2H, m), 3.23–3.21(2H, m), 3.37–3.33(2H, m), 3.47(6H, s),3.82(3H, s), 6.90–6.82(2H, m), 6.98(1H, d, J=8.4 Hz), 7.21–7.17(2H, m),7.63(1H, d, J=1.5 Hz), 7.79(1H, d, J=8.1 Hz).

Reference Example 60 tert-Butyl2-(2-chlorophenyl)ethyl[5-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-5-oxopentyl]carbamate

Using5-(5-chloropentanoyl)-1,3-dimethyl-1,3-dihydro-2H-benzimidazol-2-oneobtained in Reference Example 10 and 2-(2-chlorophenyl)ethylamineaccording to the same method as that of Reference Example 19, the titlecompound was obtained as a colorless oil.

¹H NMR (300 MHz, CDCl₃) δ 1.74–1.41(13H, m), 3.01–2.94(4H, m),3.24–3.15(2H, m), 3.44–3.39(2H, m), 3.46(3H, s), 3.47(3H, s), 6.99(1H,d, J=8.1 Hz), 7.17(3H, m), 7.35–7.32(1H, m), 7.63(1H, d, J=1.5 Hz),7.79(1H, d, J=8.1 Hz).

Reference Example 61 tert-Butyl5-(1-benzyl-2,3-dihydro-1H-indol-5-yl)-5-oxopentyl[2-(2-methoxyphenyl)ethyl]carbamate

Using tert-butyl5-(2,3-dihydro-1H-indol-5-yl)-5-oxopentyl[2-(2-methoxyphenyl)ethyl]carbamateobtained in Reference Example 50 and benzyl bromide according to thesame method as that of Reference Example 51, the title compound wasobtained as a colorless oil.

¹H NMR (400 MHz, CDCl₃) δ 1.43(9H, s), 1.51–1.68(4H, m), 2.85(4H, br.s),3.03(2H, t, J=8.3 Hz), 3.07–3.20(2H, m), 3.34(2H, br.s), 3.50(2H, t,J=8.4 Hz), 3.81(3H, s), 4.37(2H, s), 6.40(1H, d, J=8.3 Hz),6.82–6.88(2H, m), 7.08–7.20(2H, m), 7.26–7.36(5H, m), 7.70(1H, s),7.74(1H, d, J=8.3 Hz).

Reference Example 62 tert-Butyl5-(1-benzoyl-2,3-dihydro-1H-indol-5-yl)-5-oxopentyl[2-(2-methoxyphenyl)ethyl]carbamate

Using tert-butyl5-(2,3-dihydro-1H-indol-5-yl)-5-oxopentyl[2-(2-methoxyphenyl)ethyl]carbamateobtained in Reference Example 50 and benzoyl chloride according to thesame method as that of Reference Example 55, the title, compound wasobtained as a colorless oil.

¹H NMR (400 MHz, CDCl₃) δ 1.43 (9H, s), 1.51–1.70(4H, m), 2.82(2H,br.s), 2.93(2H, br.s), 3.15(2H, t, J=8.5 Hz), 3.21(2H, br.s), 3.35(2H,br.s), 3.82(3H, s), 4.13(2H, t, J=8.4 Hz), 6.82–6.88(2H, m),7.09–7.20(2H, m), 7.44–7.57(6H, m), 7.75(1H, br.s), 7.83(1H, s).

Reference Example 63 tert-Butyl5-[1-(anilinocarbonyl)-2,3-dihydro-1H-indol-5-yl]-5-oxopentyl[2-(2-methoxyphenyl)ethyl]carbamate

Using tert-butyl5-(2,3-dihydro-1H-indol-5-yl)-5-oxopentyl[2-(2-methoxyphenyl)ethyl]carbamateobtained in Reference Example 50 and phenyl isocyanate according to thesame method as that of Reference Example 55, the title compound wasobtained as colorless crystals having a melting point of 136 to 137° C.

¹H NMR (400 MHz, CDCl₃) δ 1.43(9H, s), 1.51–1.70(4H, m), 2.82(2H, br.s),2.91(2H, t, J=7.0 Hz), 3.13–3.26(4H, m), 3.35(2H, br.s), 3.81(3H, s),4.11(2H, t, J=8.4 Hz), 6.36(1H, s), 6.82–6.88(2H, m), 7.08–7.20(3H, m),7.33(2H, t, J=8.3 Hz), 7.45(2H, d, J=8.0 Hz), 7.78(1H, s), 7.81(1H, d,J=8.5 Hz), 7.98(1H, d, J=8.0 Hz).

Reference Example 64 5-Chloro-1-(4-methoxyphenyl)-1-pentanone

Using anisole (15.0 g) and 5-chlorovaleryl chloride (18.0 ml) accordingto the same method as that of Reference Example 1, the title compoundwas obtained as colorless crystals (27.3 g) having a melting point of 67to 68° C.

¹H NMR (300 MHz, CDCl₃) δ 1.80–1.95 (4H, m), 2.90–3.00 (2H, m),3.55–3.60 (2H, m), 3.86 (3H, s), 6.90–7.00 (2H, m), 7.90–8.00 (2H, m).elementary analysis as C₁₂H₁₅ClO₂ calculation value: C, 63.58; H, 6.67;N, 0.00. experimental value: C, 63.50; H, 6.67; N, 0.00.

Reference Example 65 5-(5-Chloropentanoyl)-2-methoxybenzenesulfonylchloride

5-Chloro-1-(4-methoxyphenyl)-1-pentanone (15.0 g) obtained in ReferenceExample 64 was added to chlorosulfonic acid (50 ml) by portions underice-cooling. The mixture was stirred at room temperature for 30 hours,the reaction mixture was added dropwise to a crashed ice (500 g),extracted with ethyl acetate, and washed with brine. The organic layerwas dried over anhydrous magnesium sulfate, and the solvent wasevaporated under reduced pressure to give the title compound ascolorless crystals (7.63 g) having a melting point of 69 to 70° C.

¹H NMR (200 MHz, CDCl₃) δ 1.80–2.00 (4H, m), 2.95–3.05 (2H, m),3,55–3.65 (2H, m), 4.15 (3H, s), 7.22 (1H, d, J=8.8 Hz), 8.33 (1H, dd,J=8.8, 2.2 Hz), 8.53 (1H, d, J=2.2 Hz). elementary analysis asC₁₂H₁₄Cl₂O₄S calculation value: C, 44.32; H, 4.34; N, 0.00. experimentalvalue: C, 43.77; H, 4.36; N, 0.00.

Reference Example 66 5-(5-Chloropentanoyl)-2-methoxybenzenesulfonamide

A 25% aqueous ammonium solution was added dropwise to a solution of5-(5-chloropentanoyl)-2-methoxybenzenesulfonyl chloride (3.00 g)obtained in Reference Example 65 in tetrahydrofuran (50 ml) underice-cooling. After stirring at room temperature for 30 minutes, thesolvent was evaporated under reduced pressure, extracted with ethylacetate, and washed with brine. The organic layer was dried overanhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure to give the title compound as colorless crystals (2.54g) having a melting point of 135 to 136° C.

¹H NMR (200 MHz, DMSO-d₆) δ 1.60–1.80 (4H, m), 3.06 (2H, t, J=6.2 Hz),3.69 (2H, t, J=6.2 Hz), 4.00 (3H, s), 7.28 (2H, s), 7.33 (1H, d, J=8.8Hz), 8.22 (1H, dd, J=8.8, 2.2 Hz), 8.30 (1H, d, J=2.2 Hz). elementaryanalysis as C₁₂H₁₆ClNO₄S calculation value: C, 47.14; H, 5.27; N, 4.58.experimental value: C, 47.06; H, 5.25; N, 4.49.

Reference Example 675-(5-Chloropentanoyl)-N-isopropyl-2-methoxybenzenesulfonamide

Using 5-(5-chloropentanoyl)-2-methoxybenzenesulfonyl chloride (3.50 g)obtained in Reference Example 65 and isopropylamine (1.90 ml) accordingto the same method as that of Reference Example 66, the title compoundwas obtained as colorless crystals (3.39 g) having a melting point of122 to 124° C.

¹H NMR (200 MHz, CDCl₃) δ 1.08 (6H, d, J=6.6 Hz), 1.80–2.00 (4H, m),2.95–3.05 (2H, m), 3.35–3.65 (3H, m), 4.07 (3H, s), 4.30–5.00 (1H, br),7.12 (1H, d, J=8.8 Hz), 8.21 (1H, dd, J=8.8, 2.2 Hz), 8.50 (1H, d, J=2.2Hz). elementary analysis as C₁₅H₂₂ClNO₄S calculation value: C, 51.79; H,6.37; N, 4.03. experimental value: C, 51.74; H, 6.37; N, 3.83.

Reference Example 685-Chloro-1-(2,3-dihydro-1-benzofuran-5-yl)-1-pentanone

Using 2,3-dihydro-1-benzofuran (24.5 g) and 5-chlorovaleryl chloride(34.8 g) according to the same method as that of Reference Example 1,the title compound was obtained as colorless crystals (32.4 g) having amelting point of 56 to 57° C.

¹H NMR (300 MHz, CDCl₃) δ 1.80–2.00 (4H, m), 2.90–3.00 (2H, m), 3.25,(2H, t, J=8.7 Hz), 3.55–3.65 (2H, m), 4.66 (2H, t, J=8.7 Hz), 6.79 (1H,d, J=8.2 Hz), 7.79 (1H, dd, J=8.2, 2.1 Hz), 7.84 (1H, d, J=2.1 Hz).elementary analysis as C₁₃H₁₅ClO₂ calculation value: C, 65.41; H, 6.33;N, 0.00. experimental value: C, 65.18; H, 6.33; N, 0.00.

Reference Example 695-(5-Chloropentanoyl)-2,3-dihydro-1-benzofuran-7-sulfonyl chloride

Using 5-chloro-1-(2,3-dihydro-1-benzofuran-5-yl)-1-pentanone (10.0 g)obtained in Reference Example 68 according to the same method as that ofReference Example 65, the title compound was obtained as colorlesscrystals (4.93 g) having a melting point of 72 to 73° C.

¹H NMR (200 MHz, CDCl₃) δ 1.80–2.00 (4H, m), 2.90–3.05 (2H, m), 3.41(2H, t, J=8.8 Hz), 3.55–3.65 (2H, m), 5.01 (2H, t, J=8.8 Hz), 8.15–8.20(1H, m), 8.25–8.30 (1H, m). elementary analysis as C₁₃H₁₄Cl₂O₄Scalculation value: C, 46.30; H, 4.18;. N, 0.00. experimental value: C,46.13; H, 4.17; N, 0.00.

Reference Example 705-(5-Chloropentanoyl)-2,3-dihydro-1-benzofuran-7-sulfonamide

Using 5-(5-chloropentanoyl)-2,3-dihydro-1-benzofuran-7-sulfonyl chloride(4.50 g) obtained in Reference Example 69 according to the same methodas that of Reference Example 66, the title compound was obtainedcolorless crystals (3.87 g) having a melting point of 134 to 136° C.

¹H NMR (200 MHz, DMSO-d₆) δ 1.65–1.85 (4H, m), 3.02 (2H, t, J=7.0 Hz),3.32 (2H, t, J=8.8 Hz), 3.68 (2H, t, J=7.0 Hz), 4.82 (2H, t, J=8.8 Hz),7.38 (2H, s), 8.05–8.10 (2H, m). elementary analysis as C₁₃H₁₆ClNO₄Scalculation value: C, 49.13; H, 5.07; N, 4.41. experimental value: C,48.96; H, 4.99; N, 4.15.

Reference Example 715-(5-Chloropentanoyl)-N-isopropyl-2,3-dihydro-1-benzofuran-7-sulfonamide

Using 5-(5-chloropentanoyl)-2,3-dihydro-1-benzofuran-7-sulfonyl chloride(4.50 g) obtained in Reference Example 69 and isopropylamine (3.80 ml)according to the same method as that of Reference Example 66, the titlecompound was obtained colorless crystals (6.76 g) having a melting pointof 103 to 104° C.

¹H NMR (200 MHz, CDCl₃) δ 1.11 (6H, d, J=6.6 Hz), 1.80–2.00 (4H, m),2.90–3.05 (2H, m), 3.34 (2H, t, J=8.8 Hz), 3.40–3.65 (3H, m), 4.71 (1H,d, J=7.0 Hz), 4.87 (2H, t, J=8.8 Hz), 8.00–8.10 (1H, m), 8.20–8.25 (1H,m). elementary analysis as C₁₆H22NO₄SCl calculation value: C, 53.40; H,6.16; N, 3.89. experimental value: C, 53.32; H, 6.16; N, 3.84.

Reference Example 725-Chloro-1-(2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-1-pentanone

Using 2,2-dimethylchroman (19.7 g) and 5-chlorovaleryl chloride (20.7 g)according to the same method as that of Reference Example 1, the titlecompound was obtained as colorless crystals (22.0 g) having a meltingpoint of 50 to 51° C.

¹H NMR (200 MHz, CDCl₃) δ 1.36 (6H, s), 1.80–1.95 (6H, m), 2.82 (2H, t,J=6.6 Hz), 2.80–3.00 (2H, m), 3.55–3.65 (2H, m), 6.80 (1H, d, J=9.0 Hz),7.70–7.80 (2H, m). elementary analysis as C₁₆H₂₁ClO₂ calculation value:C, 68.44; H, 7.68; N, 0.00. experimental value: C, 68.31; H, 7.54; N,0.00.

Reference Example 736-(5-Chloropentanoyl)-2,2-dimethyl-8-chromansulfonyl chloride

Using 5-chloro-1-(2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-1-pentanone(5.00 g) obtained in Reference Example 72 according to the same methodas that of Reference Example 65, the title compound was obtained as acolorless oil (1.30 g).

¹H NMR (200 MHz, CDCl₃) δ 1.50 (6H, s), 1.75–2.10 (6H, m), 2.85–3.05(4H, m), 3.55–3.65 (2H, m), 8.60 (1H, s), 8.33 (1H, s).

Reference Example 746-(5-Chloropentanoyl)-2,2-dimethyl-8-chromansulfonamide

Using 6-(5-chloropentanoyl)-2,2-dimethyl-8-chromansulfonyl chloride(1.30 g) obtained in Reference Example 73 according to the same methodas that of Reference Example 66, the title compound was obtained ascolorless crystals (630 mg) having a melting point of 148 to 149° C.

¹H NMR (300 MHz, CDCl₃) δ 1.48 (6H, s), 1.80–1.90 (4H, m), 1.95 (2H, t,J=6.9 Hz), 2.91 (2H, t, J=6.9 Hz), 2.95–3.00 (2H, m), 3.55–3.60 (2H, m),5.03 (2H, s), 7.95–8.00 (1H, m), 8.25–8.30 (1H, m).

Reference Example 755-Chloro-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-pentanone

Using 2,3-dihydro-1,4-benzodioxine. (10.0 g) and 5-chlorovalerylchloride (10.4 ml) according to the same method as that, of ReferenceExample 1, the title compound was obtained as colorless crystals (15.1g) having a melting point of 52 to 53° C.

¹H NMR (300 MHz, CDCl₃) δ 1.80–1.95 (4H, m), 2.90–3.00 (2H, m),3.55–3.60 (2H, m), 4.25–4.35 (4H, s), 6.85–6.95 (1H, m), 7.45–7.50 (2H,m). elementary analysis as C₁₃H₁₅ClO₃ calculation value: C, 61.30; H,5.94; N, 0.00. experimental value: C, 61.26; H, 5.83; N, 0.00.

Reference Example 767-(5-Chloropentanoyl)-2,3-dihydro-1,4-benzodioxine-5-sulfonamide

By using 5-chloro-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-pentanone (9.00g) obtained in Reference Example 75 and carrying out the same process asthose of Reference Examples 65 and 66 successively, the title compoundwas obtained as colorless crystals (3.88 g) having a melting point of141 to 142° C.

¹H NMR (300 MHz, CDCl₃) δ 1.80–1.95 (4H, m), 2.94 (2H, t, J=6.6 Hz),3.58 (2H, t, J=6.0 Hz), 4.30–4.45 (2H, m), 4.50–4.60 (2H, m), 5.20 (2H,s), 7.67 (1H, d, J=1.8 Hz), 7.99. (1H, d, J=1.8 Hz). elementary analysisas C₁₃H₁₆ClNO₅S. calculation value: C, 46.78; H, 4.83; N, 4.20.experimental value: C, 46.63; H, 4.83; N, 4.10.

Reference Example 77 5trans-N-({4-[(4-Oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)carbonyl]cyclohexyl}methyl)acetamide

trans-4-[(Acetylamino)methyl]cyclohexanecarboxylic acid (12.1 g) wasadded by portions to thionyl chloride (25 ml) under ice-cooling. Afterstirred at room temperature for 30 minutes, thionyl chloride wasevaporated under reduced pressure to give crude crystals oftrans-4-[(acetylamino)methyl]cyclohexanecarbonyl chloride. Then,aluminum chloride (24.0 g) was added by portions to a solution of thecrude crystals and 1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(12.1 g) in dichloromethane (30 ml) under ice-cooling. After stirring atroom temperature for 12 hours, the reaction mixture was poured into ice(300 g), extracted with ethyl acetate, and washed with brine. Theorganic layer was dried over anhydrous magnesium sulfate, and thesolvent was evaporated under reduced pressure to give the title compoundas colorless crystals (12.9 g) having a melting point of 178 to 180° C.

¹H NMR (300 MHz, CDCl₃) δ 1.05–1.20 (2H, m), 1.45–1.60 (3H, m),1.70–2.05 (4H, m), 2.01 (3H, s), 2.72 (2H, t, J=7.8 Hz), 3.03 (2H, t,J=7.8 Hz), 3.10–3.30 (5H, m), 4.13 (2H, t, J=8.4 Hz), 5.55–5.70 (1H, m),7.64 (1H, s), 7.69 (1H, s)

Reference Example 78trans-8-{[4-(Aminomethyl)cyclohexyl]carbonyl}-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Concentrated hydrochloric acid (100 ml) was added totrans-N-({4-[(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)carbonyl]cyclohexyl}methyl)acetamide(12.0 g) obtained in Reference Example 77, and the mixture was stirredat 140° C. for 12 hours. Hydrochloric acid was evaporated under reducedpressure to give white powders. Further recrystallization fromwater-isopropyl ether afforded the title compound as colorless crystals(9.40 g) having a melting point, of 255 to 257° C.

¹H NMR (200 MHz, DMSO-d₆) δ 1.00–1.95 (1H, m), 2.50–2.75 (3H, m), 2.98(2H, t, J=7.8 Hz), 3.18 (2H, t, J=8.8 Hz), 3.20–3.40 (1H, m), 3.99, (2H,t, J=8.8 Hz), 7.72 (1H, s), 7.73 (1H, s), 7.90–8.20, (3H, br).

Reference Example 79 tert-Butyl2-(4-methoxyphenyl)ethyl[5-oxo-5-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)pentyl]carbamate

Using8-(5-chloropentanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(1.00 g) obtained in Reference Example 1 and2-(4-methoxyphenyl)ethylamine (1.06 g) according to the same method asthat of Reference Example 19, the title compound (1.23 g) was obtainedas a colorless oil.

¹H NMR (300 MHz, CDCl₃) δ 1.45 (9H, s), 1.50–1.95 (4H, m), 2.65–2.80(2H, m), 2.71 (2H, t, J=7.8 Hz), 2.85–3.00 (2H, m), 3.01 (2H, t, J=7.8Hz), 3.05–3.40 (4H, m), 3.21 (2H, t, J=8.4 Hz), 3.78 (3H, s), 4.12 (2H,t, J=8.4 Hz), 6.82 (2H, d, J=8.4 Hz), 7.00–7.15 (2H, m), 7.66 (1H, s),7.70 (1H, s).

Reference Example 80 tert-Butyl2-(4-chlorophenyl)ethyl[5-oxo-5-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)pentyl]carbamate

Using8-(5-chloropentanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(1.00 g) obtained in Reference Example 1 and2-(4-chlorophenyl)ethylamine (1.06 g) according to the same method asthat of Reference Example 19, the title compound (941 mg) was obtainedas a colorless oil.

¹H NMR (300 MHz, CDCl₃) δ 1.43 (9H, s), 1.50–1.95 (4H, m), 2.65–2.85(2H, m), 2.71 (2H, t, J=7.8 Hz), 2.85–3.00 (2H, m), 3.01 (2H, t, J=7.8Hz), 3.05–3.45 (4H, m), 3.22 (2H, t, J=8.4 Hz), 4.13 (2H, t, J=8.4 Hz),7.00–7.30 (4H, m), 7.66 (1H, s), 7.70 (1H, s).

Reference Example 81 tert-Butyl2-(3-chlorophenyl)ethyl[5-oxo-5-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)pentyl]carbamate

Using8-(5-chloropentanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(1.00 g) obtained in Reference Example 1 and2-(3-chlorophenyl)ethylamine (1.06 g) according to the same method asthat of Reference Example 19, the title compound (1.19 g) was obtainedas a colorless oil.

¹H NMR (300 MHz, CDCl₃) δ 1.43 (9H, s), 1.50–1.90 (4H, m), 2.65–2.85(2H, m), 2.70 (2H, t, J=7.8 Hz), 2.85–3.00 (2H, m), 3.01 (2H, t, J=7.8Hz), 3.05–3.25 (2H, m), 3.21 (2H, t, J=8.4 Hz), 3.36 (2H, t, J=7.5 Hz),4.12 (2H, t, J=8.4 Hz), 7.00–7.20 (4H, m), 7.65 (1H, s), 7.70 (1H, s).

Reference Example 82 tert-Butyl2-(2-hydroxyphenyl)ethyl[5-oxo-5-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)pentyl]carbamate

A mixture of 8-(5-chloropentanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (1.00 g) obtained in Reference Example1, 2-(2-hydroxyphenyl)ethylamine hydrobromide (1.49 g) anddiisopropylethylamine (1.16 ml) in dimethylformaide (1 ml) was stirredat 120° C. for 1 hour. After cooled to room temperature, methanol (10ml) and triethylamine (1.43 ml) were added to the reaction mixture, asolution of di-t-butyl dicarbonate (2.24 g) in methanol (5 ml) was addeddropwise, and the mixture was stirred at room temperature for 12 hours.The solvent was evaporated under reduced pressure, the resulting residuewas purified by silica gel chromatography (eluting solvent; hexane:ethyl acetate=2:1), and the solvent was evaporated to give the titlecompound as colorless crystals (687 mg) having a melting point of 154 to155° C.

¹H NMR (300 MHz, CDCl₃) δ 1.48 (9H, s), 1.55–1.85 (4H, m), 2.71 (2H, t,J=7.8 Hz), 2.83 (2H, t, J=7.5 Hz), 2.94 (2H, t, J=7.5 Hz), 3.00 (2H, t,J=7.8 Hz), 3.15–3.35 (6H, m), 4.12 (2H, t, J=8.4 Hz), 6.70–7.15 (4H, m),7.66 (1H, s), 7.70 (1H, s), 7.40–7.65 (1H, br). elementary analysis asC₂₉H₃₆N₂O₅.0.2H₂O calculation value: C, 70.19; H, 7.39; N, 5.65.experimental value: C, 70.34; H, 7.35; N, 5.66.

Reference Example 83 tert-Butyl2-(2,6-dichlorophenyl)ethyl[5-oxo-5-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)pentyl]carbamate

Using8-(5-chloropentanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(1.00 g) obtained in Reference Example 1 and2-(2,6-dichlorophenyl)ethylamine (650 mg) according to the same methodas that of Reference Example 19, the title compound (1.08 g) wasobtained as a colorless oil.

¹H NMR (300 MHz, CDCl₃) δ 1.42 (9H, s), 1.50–1.80 (4H, m), 1.80–1.95(2H, m), 2.71 (2H, t, J=7.8 Hz), 2.85–3.65 (10H, m), 4.13 (2H, t, J=8.4Hz), 7.10 (1H, t, J=7.8 Hz), 7.25–7.30 (2H, m), 7.68 (1H, s), 7.72 (1H,s).

Reference Example 84 tert-Butyl2-(2,3-dimethoxyphenyl)ethyl[5-oxo-5-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)pentyl]carbamate

Using8-(5-chloropentanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(1.00 g) obtained in Reference Example 1 and2-(2,3-dimethoxyphenyl)ethylamine (620 mg) according to the same methodas that of Reference Example 19, the title compound (1.13 g) wasobtained as a colorless oil.

¹H NMR (300 MHz, CDCl₃) δ 1.46 (9H, s), 1.50–1.90 (6H, m), 2.71 (2H, t,J=7.8 Hz), 2.75–3.45 (10H, m), 3.84 (3H, s), 3.86 (3H, s), 4.12 (2H, t,J=8.4 Hz), 6.70–6.85 (2H, m), 6.98 (1H, t, J=7.8 Hz), 7.67 (1H, s), 7.72(1H, s).

Reference Example 85 tert-Butyl5-oxo-5-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)pentyl[2-(2-thienyl)ethyl]carbamate

Using8-(5-chloropentanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(1.00 g) obtained in Reference Example 1 and 2-(2-thienyl)ethylamine(435 mg) according to the same method as that of Reference Example 19,the title compound (1.44 g) was obtained as a colorless oil.

¹H NMR (300 MHz, CDCl₃) δ 1.38 (9H, s), 1.40–1.85, (6H, m), 2.63 (2H, t,J=7.8 Hz), 2.80–3.55 (10H, m), 4.05 (2H, t, J=7.2 Hz), 6.70–6.80 (1H,m), 6.80–6.90 (1H, m), 7.00–7.10 (1H, m), 7.61 (1H, s), 7.65 (1H, s).

Reference Example 86 tert-Butyl5-(2,3-dihydro-1,4-benzodioxin-6-yl)-5-oxopentyl[2-(2-methoxyphenyl)ethyl]carbamate

Using 5-chloro-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-pentanone (1.00 g)obtained in Reference Example 75 and 2-(2-methoxyphenyl)ethylamine (594mg) according to the same method as that of Reference Example 19, thetitle compound (1.84 g) was obtained as a colorless oil.

¹H NMR (300 MHz, CDCl₃) δ 1.43 (9H, s), 1.50–2.00 (4H, m), 2.75–3.60(12H, m), 3.82 (3H, s), 6.80–7.25 (5H, m), 7.60–7.65 (1H, m), 7.79 (1H,dd, J=8.2, 1.5 Hz).

Reference Example 87 tert-Butyl5-[3-(aminosulfonyl)-4-methoxyphenyl]-5-oxopentyl(2-phenylethyl)carbamate

Using 5-(5-chloropentanoyl)-2-methoxybenzenesulfonamide (900 mg)obtained in Reference Example 66 and 2-phenylethylamine (713 mg)according to the same method as that of Reference Example 19, the titlecompound was obtained as colorless crystals (1.07 g) having a meltingpoint of 121 to 122° C.

¹H NMR (300 MHz, CDCl₃) δ 1.30–1.75 (13H, m), 2.75–2.85 (2H, m),2.90–3.00 (2H, m), 3.05–3.25 (2H, m), 3.36 (2H, t, J=7.8 Hz), 4.08 (3H,s), 5.37 (2H, s), 7.10 (1H, d, J=8.8 Hz), 7.10–7.30 (5H, m), 8.16 (1H,dd, J=8.8, 2.1 Hz), 8.44 (1H, d, J=2.1 Hz). elementary analysis asC₂₅H₃₄N₂O₆S calculation value: C, 61.20; H, 6.99; N, 5.71. experimentalvalue: C, 61.20; H, 7.02; N, 5.66.

Reference Example 88 tert-Butyl5-[3-(aminosulfonyl)-4-methoxyphenyl]-5-oxopentyl[2-(2-methoxyphenyl)ethyl]carbamate

Using 5-(5-chloropentanoyl)-2-methoxybenzenesulfonamide (800 mg)obtained in Reference Example 66 and 2-(2-methoxyphenyl)ethylamine (792mg) according to the same method as that of Reference Example 19, thetitle compound (740 mg) was obtained as a colorless oil.

¹H NMR (200 MHz, CDCl₃) δ 1.30–1.80 (13H, m), 2.80 (2H, t, J=7.6 Hz),2.90–3.00 (2H, m), 3.05–3.25 (2H, m), 3.33 (2H, t, J=7.6 Hz), 3.81 (3H,s), 4.07 (3H, s), 5.66 (2H, s), 6.80–6.95 (2H, m), 7.00–7.25 (3H, m),8.10–8.20 (1H, m), 8.40–8.45 (1H, m).

Reference Example 89 tert-Butyl5-[3-(aminosulfonyl)-4-methoxyphenyl]-5-oxopentyl[2-(2-chlorophenyl)ethyl]carbamate

Using 5-(5-chloropentanoyl)-2-methoxybenzenesulfonamide (900 mg)obtained in Reference Example 66 and 2-(2-chlorophenyl)ethylamine (915mg) according to the same method as that of Reference Example 19, thetitle compound was obtained as colorless crystals (1.07 g) having amelting point of 113 to 114° C.

¹H NMR (300 MHz, CDCl₃) δ 1.30–1.80 (13H, m), 2.90–3.00 (4H, m),3.05–3.25 (2H, m), 3.38 (2H, t, J=7.6 Hz), 4.09 (3H, s), 5.43 (2H, s),7.05–7.40 (5H, m), 8.16 (1H, dd, J=8.7, 2.1 Hz), 8.43 (1H, d, J=2.1 Hz).elementary analysis as C₂₅H₃₃ClN₂O₆S calculation value: C, 57.19; H,6.33; N, 5.34. experimental value: C, 57.07; H, 6.34; N, 5.22.

Reference Example 90 tert-Butyl5-{3-[(isopropylamino)sulfonyl]-4-methoxyphenyl}-5-oxopentyl[2-(2-methoxyphenyl)ethyl]carbamate

Using 5-(5-chloropentanoyl)-N-isopropyl-2-methoxybenzenesulfonamide (800mg) obtained in Reference Example 67 and 2-(2-methoxyphenyl)ethylamine(696 mg) according to the same method as that of Reference Example 19,the title compound (1.36 g) was obtained as a colorless oil.

¹H NMR (200 MHz, CDCl₃) δ 1.07 (6H, d, J=6.6 Hz), 1.40–1.80 (13H, m),2.80–3.50 (9H, m), 3.83 (3H, s), 4.07 (3H, s), 5.21 (1H, d, J=7.2 Hz),6.80–6.95 (2H, m), 7.05–7.25 (3H, m), 8.20 (1H, dd, J=8.8, 2.2 Hz), 8.51(1H, d, J=2.2 Hz).

Reference Example 91 tert-Butyl2-(2-chlorophenyl)ethyl(5-{3-[(isopropylamino)sulfonyl]-4-methoxyphenyl}-5-oxopentyl)carbamate

Using 5-(5-chloropentanoyl)-N-isopropyl-2-methoxybenzenesulfonamide (800mg) obtained in Reference Example 67 and 2-(2-chlorophenyl)ethylamine(716 mg) according to the same method as that of Reference Example 19,the title compound (1.28 g) was obtained as a colorless oil.

¹H NMR (200 MHz, CDCl₃) δ 1.07 (6H, d, J=6.6 Hz), 1.35–1.80 (13H, m),2.85–3.50 (9H, m), 4.07 (3H, s), 4.87 (1H, d, J=6.8 Hz), 7.05–7.40 (5H,m), 8.20 (1H, dd, J=8.8, 2.2 Hz), 8.50 (1H, d, J=2.2 Hz).

Reference Example 92 tert-Butyl5-[7-(aminosulfonyl)-2,3-dihydro-1-benzofuran-5-yl]-5-oxopentyl[2-(2-methoxyphenyl)ethyl]carbamate

Using 5-(5-chloropentanoyl)-2,3-dihydro-1-benzofuran-7-sulfonamide (800mg) obtained in Reference Example 70 and 2-(2-methoxyphenyl)ethylamine(762 mg) according to the same method as that of Reference Example 19,the title compound (990 mg) was obtained as a colorless oil.

¹H NMR (200 MHz, CDCl₃) δ 1.20–1.80 (13H, m), 2.75–3.00 (5H, m),3.05–3.40 (5H, m), 3.82 (3H, s), 4.87 (2H, t, J=8.6 Hz), 5.50 (2H, s),6.80–6.90 (2H, m), 7.00–7.25 (2H, m), 7.99 (1H, s), 8.17 (1H, s).

Reference Example 93 tert-Butyl5-[7-(aminosulfonyl)-2,3-dihydro-1-benzofuran-5-yl]-5-oxopentyl[2-(2-chlorophenyl)ethyl]carbamate

Using 5-(5-chloropentanoyl)-2,3-dihydro-1-benzofuran-7-sulfonamide (800mg) obtained in Reference Example 70 and 2-(2-chlorophenyl)ethylamine(784 mg) according to the same method as that of Reference Example 19,the title compound was obtained as colorless crystals (1.04 g) having amelting point of 114 to 115° C.

¹H NMR (200 MHz, CDCl₃) δ 1.25–1.80 (13H, m), 2.80–3.45 (10H, m), 4.90(2H, t, J=8.8 Hz), 5.29 (2H, s), 7.10–7.40 (4H, m), 8.02 (1H, s), 8.20(1H, s). elementary analysis as C₂₆H₃₃ClN₂O₆S calculation value: C,58.14; H, 6.19; N, 5.22. experimental value: C, 57.93; H, 6.22; N, 5.12.

Reference Example 94 tert-Butyl5-{7-[(isopropylamino)sulfonyl]-2,3-dihydro-1-benzofuran-5-yl}-5-oxopentyl[2-(2-methoxyphenyl)ethyl]carbamate.

Using5-(5-chloropentanoyl)-N-isopropyl-2,3-dihydro-1-benzofuran-7-sulfonamide(1.00 g) obtained in Reference Example 71 and2-(2-methoxyphenyl)ethylamine (841 mg) according to the same method asthat of Reference Example 19, the title compound (1.00 g) was obtainedas a colorless oil.

¹H NMR (300 MHz, CDCl₃) δ 1.09 (6H, d, J=6.3 Hz), 1.35–1.75 (13H, m),2.75–3.50 (11H, m), 3.82 (3H, s), 4.75–4.90 (3H, m), 6.80–6.90 (2H, m),7.05–7.20 (2H, m), 8.03 (1H, s), 8.23 (1H, s).

Reference Example 95 tert-Butyl2-(2-chlorophenyl)ethyl(5-{7-[(isopropylamino)sulfonyl]-2,3-dihydro-1-benzofuran-5-yl}-5-oxopentyl)carbamate

Using5-(5-chloropentanoyl)-N-isopropyl-2,3-dihydro-1-benzofuran-7-sulfonamide(2.00 g) obtained in Reference. Example 71 and2-(2-chlorophenyl)ethylamine (1.73 g) according to the same method asthat of Reference Example 19, the title compound (2.10 g) was obtainedas a colorless oil.

¹H NMR (300 MHz, CDCl₃) δ 1.10 (6H, d, J=6.6 Hz), 1.30–2.00 (13H, m),2.80–3.50 (11H, m), 4.75–4.90 (3H, m), 7.10–7.40 (4H, m), 8.04 (1H, s),8.23 (1H, s).

Reference Example 96 tert-Butyl5-[8-(aminosulfonyl)-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl]-5-oxopentyl[2-(2-chlorophenyl)ethyl]carbamate

Using 6-(5-chloropentanoyl)-2,2-dimethyl-8-chromansulfonamide (600 mg)obtained in Reference Example 74 and 2-(2-chlorophenyl)ethylamine (548mg) according to the same method as that of Reference Example 19, thetitle compound (715 mg) was obtained as a colorless oil.

¹H NMR (200 MHz, CDCl₃) δ 1.30–1.90 (13H, m), 1.47 (6H, s), 1.93 (2H, t,J=6.6 Hz), 2.80–3.30 (8H, m), 3.39 (2H, t, J=6.6 Hz), 5.26 (2H, s),7.10–7.40 (4H, m), 7.92 (1H, s), 8.26 (1H, s)

Reference Example 97 tert-Butyl5-[8-(aminosulfonyl)-2,3-dihydro-1,4-benzodioxin-6-yl]-5-oxopentyl(2-phenylethyl)carbamate

Using 7-(5-chloropentanoyl)-2,3-dihydro-1,4-benzodioxine-5-sulfonamide(800 mg) obtained in Reference Example 76 and phenethylamine (582 mg)according to the same method as that of Example 19, the title compound(1.05 g) was obtained as a colorless oil.

¹H NMR (300 MHz, CDCl₃) δ 1.35–1.80 (13H, m), 2.75–2.95 (4H, m),3.05–3.25 (2H, m), 3.35 (2H, t, J=7.5 Hz), 4.30–4.40 (2H, m), 4.45–4.55(2H, m), 5.40–5.50 (2H, m), 7.10–7.35 (5H, m), 7.64 (1H, s), 7.98 (1H,s).

Reference Example 98 tert-Butyl5-[8-(aminosulfonyl)-2,3-dihydro-1,4-benzodioxin-6-yl]-5-oxopentyl[2-(2-methoxyphenyl)ethyl]carbamate

Using 7-(5-chloropentanoyl)-2,3-dihydro-1,4-benzodioxine-5-sulfonamide(800 mg) obtained in Reference Example 76 and2-(2-methoxyphenyl)ethylamine (726 mg) according to the same method asthat of Example 19, the title compound (820 mg) was obtained as acolorless oil.

¹H NMR (300 MHz, CDCl₃) δ 1.35–1.75 (13H, m), 2.80 (2H, t, J=7.2 Hz),2.85–3.00 (2H, m), 3.05–3.25 (2H, m), 3.32 (2H, t, J=7.2 Hz), 3.82 (3H,s), 4.30–4.40 (2H, m), 4.45–4.55 (2H, m), 5.31 (2H, s), 6.80–7.20 (4H,m), 7.67 (1H, s), 8.01 (1H, s).

Reference Example 99 tert-Butyl5-[8-(aminosulfonyl)-2,3-dihydro-1,4-benzodioxin-6-yl]-5-oxopentyl[2-(2-chlorophenyl)ethyl]carbamate

Using 7-(5-chloropentanoyl)-2,3-dihydro-1,4-benzodioxine-5-sulfonamide(800 mg) obtained in Reference Example 76 and2-(2-chlorophenyl)ethylamine (746 mg) according to the same method asthat of Example 19, the title compound (1.08 g) was obtained as acolorless oil.

¹H NMR (300 MHz, CDCl₃) δ 1.30–1.80 (13H, m), 2.80–3.00 (4H, m),3.05–3.25 (2H, m), 3.39 (2H, t, J=7.2 Hz), 4.30–4.40 (2H, m), 4.45–4.55(2H, m), 5.25–5.50 (2H, m), 7.05–7.40 (4H, m), 7.66 (1H, s), 7.99 (1H,s).

Reference Example 100 tert-Butyl5-{4-methoxy-3-[(methylsulfonyl)amino]phenyl}-5-oxopentyl(2-phenylethyl)carbamate

Using N-[5-(5-chloropentanoyl)-2-methoxyphenyl]methanesulfonamide (1.00g) obtained in Reference Example 13 and phenethylamine (786 mg)according to the same method as that of Reference Example 19, the titlecompound (1.32 g) was obtained as a colorless oil.

¹H NMR (200 MHz, CDCl₃) δ 1.44(9H, s), 1.50–1.90(4H, m), 2.75–3.45(8H,m), 2.99(3H, s), 3.96(3H, s), 6.80–7.00(2H, m), 7.10–7.35(5H, m),7.75–7.85(1H, m), 8.05–8.15(1H, m).

Reference Example 101 tert-Butyl5-{4-methoxy-3-[(methylsulfonyl)amino]phenyl}-5-oxopentyl[2-(2-methoxyphenyl)ethyl]carbamate

Using N-[5-(5-chloropentanoyl)-2-methoxyphenyl]methanesulfonamide (1.00g) obtained in Reference Example 13 and 2-(2-methoxyphenyl)ethylamine(1.42 g) according to the same method as that of Reference Example 19,the title compound (550 mg) was obtained as a colorless oil.

¹H NMR (300 MHz, CDCl₃) δ 1.43(9H, s), 1.50–1.80(4H, m), 2.75–3.40(4H,m), 2.99(3H, s), 3.83(3H, s), 3.05–3.45 (4H, m), 3.96(3H, s),6.80–6.90(3H, m), 6.96(1H, d, J=8.4 Hz), 7.05–7.25(2H, m), 7.80(1H, dd,J=8.4, 1.8 Hz), 8.10(1H, d, J=1.8 Hz).

Reference Example 102 tert-Butyl2-(2-chlorophenyl)ethyl(5-{4-methoxy-3-[(methylsulfonyl)amino]phenyl}-5-oxopentyl)carbamate

Using N-[5-(5-chloropentanoyl)-2-methoxyphenyl]methanesulfonamide (1.00g) obtained in Reference Example 13 and 2-(2-chlorophenyl)ethylamine(1.46 g) according to the same method as that of Reference Example 19,the title compound (1.52 g) was obtained as a colorless oil.

¹H NMR (200 MHz, CDCl₃) δ 1.41(9H, s), 1.45–1.80(4H, m), 2.75–3.50(6H,m), 3.00(3H, s), 3.41(2H, t, J=7.4 Hz), 3.96(3H, s), 6.90–7.00(2H, m),7.10–7.40(4H, m), 7.75–7.85(1H, m), 8.05–8.10(1H, m).

Reference Example 103 tert-Butyl6-{4-methoxy-3-[(methylsulfonyl)amino]phenyl}-6-oxohexyl(2-phenylethyl)carbamate

Using N-[5-(6-bromopentanoyl)-2-methoxyphenyl]methanesulfonamide (1.00g) obtained in Reference Example 14 and phenethylamine (641 mg)according to the same method as that of Reference Example 19, the titlecompound (918 mg) was obtained as a colorless oil.

¹H NMR (300 MHz, CDCl₃) δ 1.30–1.90(6H, m), 1.44(9H, s), 2.75–2.85(2H,m), 2.91(2H, t, J=7.5 Hz), 2.99(3H, s), 3.00–3.20(2H, m), 3.30–3.45(2H,m), 3.96(3H, s), 6.90(1H, s), 6.97(1H, d, J=8.4 Hz), 7.15–7.30(5H, m),7.81(1H, dd, J=8.4, 1.8 Hz), 8.12(1H, d, J=1.8 Hz).

Reference Example 104 tert-Butyl6-{4-methoxy-3-[(methylsulfonyl)amino]phenyl}-6-oxohexyl[2-(2-methoxyphenyl)ethyl]carbamate

Using N-[5-(6-bromopentanoyl)-2-methoxyphenyl]methanesulfonamide (1.00g) obtained in Reference Example 14 and 2-(2-methoxyphenyl)ethylamine(800 mg) according to the same method as that of Reference Example 19,the title compound (1.00 g) was obtained as a colorless oil.

¹H NMR (300 MHz, CDCl₃) δ 1.25–1.60(4H, m), 1.43(9H, s), 1.73(2H,quintet, J=7.5 Hz), 2.75–2.90(2H, m), 2.91(2H, t, J=7.5 Hz), 2.99(3H,s), 3.00–3.20(2H, m), 3.30–3.45(2H, m), 3.82(3H, s), 3.96(3H, s),6.80–7.20(6H, m), 7.80(1H, dd, J=8.4, 1.8 Hz), 8.10(1H, d, J=1.8 Hz).

Reference Example 105 tert-Butyl2-(2-chlorophenyl)ethyl(6-{4-methoxy-3-[(methylsulfonyl)amino]phenyl}-6-oxohexyl)carbamate

Using N-[5-(6-bromopentanoyl)-2-methoxyphenyl]methanesulfonamide (1.00g) obtained in Reference Example 14 and 2-(2-chlorophenyl)ethylamine(823 mg) according to the same method as that of Reference Example 19,the title compound (1.03 g) was obtained as a colorless oil.

¹H NMR (300 MHz, CDCl₃) δ 1.25–1.90(6H, m), 1.41(9H, s), 2.90–3.25(6H,m), 2.99(3H, s), 3.40(2H, t, J=7.5 Hz), 3.97(3H, s), 6.89(1H, s),6.97(1H, d, J=8.4 Hz), 7.10–7.40(4H, m), 7.80(1H, dd, J=8.4, 1.8 Hz),8.10(1H, d, J=1.8 Hz).

Reference Example 106 tert-Butyl5-(1H-indol-3-yl)-5-oxopentyl(2-phenylethyl)carbamate

Using 5-chloro-1-(1H-indol-3-yl)-1-pentanone (1.00 g). obtained inReference Example 15 and 2-phenylethylamine (1.03 g) according to thesame method as that of Reference Example 19, the title compound wasobtained as colorless crystals (1.10 g) having a melting point of 100 to108° C.

¹H NMR (300 MHz, CDCl₃) δ 1.44(9H, s), 1.50–2.10(4H, m), 2.70–2.90(4H,m), 3.05–3.25(2H, m), 3.30–4.45(2H, m), 7.10–7.45(8H, m), 7.70–7.90(1H,m), 8.35–8.45(1H, m), 9.05–9.35(1H, br).

Reference Example 107 tert-Butyl5-(1H-indol-3-yl)-5-oxopentyl[2-(2-methoxyphenyl)ethyl]carbamate

Using 5-chloro-1-(1H-indol-3-yl)-1-pentanone (1.00 g) obtained inReference Example 15 and 2-(2-methoxyphenyl)ethylamine (1.28 g)according to the same method as that of Reference Example 19, the titlecompound (901 mg) was obtained as a colorless oil.

¹H NMR (300 MHz, CDCl₃) δ 1.44(9H, s), 1.50–1.80(4H, m), 2.70–2.90(4H,m), 3.10–3.45(4H, m), 3.65–3.85(3H, m), 6.75–6.90(2H, m), 7.00–7.45(5H,m), 7.60–7.90(1H, m), 8.35–8.40(1H, m), 9.70–10.00(1H, br).

Reference Example 108 tert-Butyl2-(2-chlorophenyl)ethyl[5-(1H-indol-3-yl)-5-oxopentyl]carbamate

Using 5-chloro-1-(1H-indol-3-yl)-1-pentanone (1.00 g) obtained inReference Example 15 and 2-(2-chlorophenyl)ethylamine (1.32 g) accordingto the same method as that of Reference Example 19, the title compoundwas obtained as colorless crystals (1.10 g) having a melting point of 97to 99° C.

¹H NMR (300 MHz, CDCl₃) δ 1.42(9H, s), 1.50–1.80(4H, m), 2.70–3.50(6H,m), 3.41(2H, t, J=7.5 Hz), 7.05–7.45(7H, m), 7.65–7.90(1H, m),8.35–8.45(1H, m), 9.20–9.40(1H, br).

Reference Example 109 tert-Butyl 6-(1H-indol-3-yl)-6-oxohexyl(2-phenylethyl)carbamate

Using 6-bromo-1-(1H-indol-3-yl)-1-hexanone (1.00 g) obtained inReference Example 16 and 2-phenylethylamine (824 mg) according to thesame method as that of Reference Example 19, the title compound wasobtained as colorless crystals (938 mg) having a melting point of 83 to85° C.

¹H NMR (200 MHz, CDCl₃) δ 1.20–1.85(6H, m), 1.44(9H, s), 2.70–2.90(4H,m), 3.05–3.25(2H, m), 3.37(2H, t, J=7.5 Hz), 7.10–7.45(8H, m),7.75–7.85(1H, m), 8.35–8.45(1H, m), 8.90–9.30(1H, br).

Reference Example 110 tert-Butyl6-(1H-indol-3-yl)-6-oxohexyl[2-(2-methoxyphenyl)ethyl]carbamate

Using 6-bromo-1-(1H-indol-3-yl)-1-hexanone (1.00 g) obtained inReference Example 16 and 2-(2-methoxyphenyl)ethylamine (1.03 g)according to the same method as that of Reference Example 19, the titlecompound was obtained as colorless crystals (788 mg) having a meltingpoint of 133 to 135° C.

¹H NMR (200 MHz, CDCl₃) δ 1.20–1.85(6H, m), 1.43(9H, s), 2.70–2.90(4H,m), 3.05–3.25(2H, m), 3.34(2H, t, J=7.2 Hz), 3.79(3H, s), 6.75–6.90(2H,m), 7.00–7.45(5H, m), 7.75–7.85(1H, m), 8.35–8.45(1H, m), 9.15–9.40(1H,br).

Reference Example 111 tert-Butyl2-(2-chlorophenyl)ethyl[6-(1H-indol-3-yl)-6-oxohexyl]carbamate

Using 6-bromo-1-(1H-indol-3-yl)-1-hexanone (1.00 g) obtained inReference Example 16 and 2-(2-chlorophenyl)ethylamine (1.03 g) accordingto the same method as that of Reference Example 19, the title compoundwas obtained as colorless crystals (788 mg) having a melting point of104 to 105° C.

¹H NMR (200 MHz, CDCl₃) δ 1.20–1.85(6H, m), 1.42(9H, s), 2.70–3.25(6H,m), 3.40(2H, t, J=7.2 Hz), 7.05–7.45(7H, m), 7.70–7.90(1H, m),8.35–8.45(1H, m), 9.25–9.80(1H, br).

Reference Example 112 tert-Butyl5-oxo-5-(2-thienyl)pentyl(2-phenylethyl)carbamate

Using 5-chloro-1-(2-thienyl)-1-pentanone (1.00 g) obtained in ReferenceExample 17 and 2-phenylethylamine (1.19 g) according to the same methodas that of Reference Example 19, the title compound was obtained ascolorless crystals (1.08 g) having a melting point of 49 to 50° C.

¹H NMR (300 MHz, CDCl₃) δ 1.44(9H, s), 1.45–1.80(4H, m), 2.75–2.95(4H,m), 3.05–3.45(4H, m), 7.10–7.35(6H, m), 7.12(1H, dd, J=5.0, 0.9 Hz),7.71(1H, s).

Reference Example 113 tert-Butyl2-(2-methoxyphenyl)ethyl[5-oxo-5-(2-thienyl)pentyl]carbamate

Using 5-chloro-1-(2-thienyl)-1-pentanone (1.00 g) obtained in ReferenceExample 17 and 2-(2-methoxyphenyl)ethylamine (1.49 g) according to thesame method as that of Reference Example 19, the title compound (1.45 g)was obtained as a colorless oil.

¹H NMR (300 MHz, CDCl₃) δ 1.43(9H, s), 1.43–1.85(4H, m), 2.75–2.95(4H,m), 3.05–3.45(4H, m), 3.82(3H, s), 6.80–6.90(2H, m), 7.05–7.25(3H, m),7.60–7.75(2H, m).

Reference Example 114 tert-Butyl2-(2-chlorophenyl)ethyl[5-oxo-5-(2-thienyl)pentyl]carbamate

Using 5-chloro-1-(2-thienyl)-1-pentanone (1.00 g) obtained in ReferenceExample 17 and 2-(2-chlorophenyl)ethylamine (1.53 g) according to thesame method as that of Reference Example 19, the title compound (1.47 g)was obtained as a pale yellow oil.

¹H NMR (300 MHz, CDCl₃) δ 1.41(9H, s), 1.45–1.80(4H, m), 2.85–3.30(4H,m), 3.05–3.30 (2H, m), 3.41(2H, t, J=7.2 Hz), 7.05–7.40(5H, m), 7.62(1H,dd, J=5.0, 0.9 Hz), 7.71(1H, s).

Reference Example 115 tert-Butyl6-oxo-6-(2-thienyl)hexyl(2-phenylethyl)carbamate

Using 6-bromo-1-(2-thienyl)-1-hexanone (1.00 g) obtained in ReferenceExample 18 and 2-phenylethylamine (1.53 g) according to the same methodas that of Reference Example 19, the title compound (1.47 g) wasobtained as a pale yellow oil.

¹H NMR (300 MHz, CDCl₃) δ 1.25–1.60(4H, m), 1.44(9H, s), 1.75(2H,quintet, J=7.5 Hz), 2.75–2.90(2H, m), 2.89(2H, t, J=7.5 Hz),3.05–3.25(2H, m), 3.50–3.65(2H, m), 7.12(1H, dd, J=5.0, 3.6 Hz),7.15–7.35(5H, m), 7.61(1H, dd, J=5.0, 0.9 Hz), 7.70(1H, dd, J=3.6, 0.9Hz).

Reference Example 116 tert-Butyl2-(2-methoxyphenyl)ethyl[6-oxo-6-(2-thienyl)hexyl]carbamate

Using 6-bromo-1-(2-thienyl)-1-hexanone (1.00 g) obtained in ReferenceExample 18 and 2-(2-methoxyphenyl)ethylamine (1.16 g) according to thesame method as that of Reference Example 19, the title compound (884 mg)was obtained as a colorless oil.

¹H NMR (300 MHz, CDCl₃) δ 1.20–1.65(4H, m), 1.43(9H, s), 1.70–1.85(2H,m), 2.75–2.90(2H, m), 2.89(2H, t, J=7.2 Hz), 3.05–3.25(2H, m),3.25–3.40(2H, m), 3.82(3H, s), 6.83(1H, d, J=7.5 Hz), 6.88(1H, dd,J=7.2, 0.9 Hz), 7.05–7.25(2H, m), 7.12(1H, dd, J=4.8, 3.9 Hz), 7.62(1H,dd, J=4.8, 1.2 Hz), 7.70(1H, dd, J=3.9, 1.2 Hz).

Reference Example 117 tert-Butyl2-(2-chlorophenyl)ethyl[6-oxo-6-(2-thienyl)hexyl]carbamate

Using 6-bromo-1-(2-thienyl)-1-hexanone (1.00 g) obtained in ReferenceExample 18 and 2-(2-methoxyphenyl)ethylamine (1.19 g) according to thesame method as that of Reference Example 19, the title compound (1.07 g)was obtained as a colorless oil.

¹H NMR (300 MHz, CDCl₃) δ 1.25–1.65(4H, m), 1.43(9H, s), 1.65–1.85(2H,m), 2.80–3.25(4H, m), 2.89(2H, t, J=7.5 Hz), 3.40(2H, t, J=7.5 Hz),7.05–7.40(5H, m), 7.60–7.75(2H, m).

Reference Example 118 tert-Butyl(±)-5-oxo-5-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)pentyl(1,2,3,4-tetrahydro-1-naphthalenyl)carbamate

Using8-(5-chloropentanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(500 mg) obtained in Reference Example 1 and(±)-1,2,3,4-tetrahydro-1-naphthalenylamine (755 mg) according to thesame method as that of Reference Example 19, the title compound (528 mg)was obtained as a pale yellow oil.

¹H NMR (200 MHz, CDCl₃) δ 1.10–2.10 (19H, m), 2.60–3.05(9H, m), 3.21(2H,t, J=8.4 Hz), 4.13(2H, t, J=8.8 Hz), 7.00–7.20(4H, m), 7.60–7.70(2H, m).

Reference Example 119 tert-Butyl(±)-1,2-diphenylethyl[5-oxo-5-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)pentyl]carbamate

Using8-(5-chloropentanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(1.00 g) obtained in Reference Example 1 and (±)-1,2-diphenylethylamine(2.02 g) according to the same method as that of Reference Example 19,the title compound (837 mg) was obtained as a pale yellow oil.

¹H NMR (200 MHz, CDCl₃) δ 1.10–1.60(6H, m), 1.31(9H, s), 1.70–2.00(2H,m), 2.71(2H, t, J=7.6 Hz), 2.80–3.10(3H, m), 3.15–3.35(3H, m),3.55–3.65(1H, m), 4.13(2H, t, J=8.8 Hz), 7.10–7.40(10H, m),7.60–7.75(2H, m).

Reference Example 1205-Chloro-1-[3-(trifluoroacetyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]-1-pentanone

Aluminum chloride (17 g, 130 mmol) was added by portions to a solutionof 3-(trifluoroacetyl)-2,3,4,5-tetrahydro-1H-3-benzazepine (15.0 g) and5-chlorovaleryl chloride (8.8 ml) in 1,2-dichloroethane (40 ml) underice-cooling. After stirring at room temperature for 30 minutes, thereaction mixture was poured into ice (500 g), extracted with ethylacetate, and washed with brine. The organic layer was dried overanhydrous magnesium sulfate, the solvent was evaporated under reducedpressure, and the residue was crystallized from ethanol-diethyl ether togive a pale yellow solid (15.2 g). Further recrystallization fromethanol-diethylether afforded colorless crystals (13.2 g) as the titlecompound.

¹H NMR (200 MHz, CDCl₃) δ 1.87–1.91 (4H, m), 2.97–3.08 (6H, m), 3.59(2H, t, J=6.2 Hz), 3.70–3.81 (4H, m), 7.26 (1H, s), 7.75 (2H, m).

Reference Example 1215-Chloro-1-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-1-pentanone

Potassium carbonate (9.2 g, 66.3 mmol) was added to a solution of5-chrolo-1-[3-(trifluoroacetyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]-1-pentanone(8.0 g) obtained in Reference Example 120 in methanol (40 ml)-water (40ml). After stirring at room temperature for 60 minutes, the solvent wasevaporated under reduced pressure, water (100 g) was added, extractedwith ethyl acetate, and washed with brine. The organic layer was driedover anhydrous sodium sulfate, and the solvent was evaporated underreduced pressure to give an oil (6.9 g).

¹H NMR (200 MHz, CDCl₃) δ 1.88 (4H, m), 2.35 (1H, br), 2.97 (10H, m),3.58 (2H, m), 7.16–7.20 (1H, m), 7.69 (2H, m).

Reference Example 1221-(3-Acetyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-5-chloro-1-pentanone

Acetyl chloride (679 μl) was added to a solution of5-chloro-1-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-1-pentanone (2.2 g)obtained in Reference Example 121 and triethylamine (1.67 ml) intetrahydrofuran (30 ml). After stirring at room temperature for 60minutes, water (50 g) was added, extracted with ethyl acetate, andwashed with brine. The organic layer was dried over anhydrous sodiumsulfate, the solvent was evaporated under reduced pressure, and theresidue was purified by silica gel column chromatography to give an oil(2.54 g).

¹H NMR (200 MHz, CDCl₃) δ 1.89 (4H, m), 2.19 (3H, s), 2.99 (6H, m), 3.59(4H, m), 3.74 (2H, m), 7.21–7.27 (1H, m), 7.74(2H, m).

Reference Example 1235-Chloro-1-[3-(methylsulfonyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]-1-pentanone

Methylsulfonyl chloride (804 μl) was added to a solution of5-chloro-1-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-1-pentanone (2.4 g)obtained in Reference Example 121 and triethylamine (1.67 ml) intetrahydrofuran (30 ml). After stirring at room temperature for 60minutes, water (50 g) was added, extracted with ethyl acetate, andwashed with brine. The organic layer was dried over anhydrous sodiumsulfate, the solvent was evaporated under reduced pressure to give apale yellow solid (2.2 g). Further recrystallization fromethanol-diethyl ether afforded the title compound as colorless crystals(1.92 g).

¹H NMR (200 MHz, CDCl₃) δ 1.89 (4H, m), 2.80 (3H, s), 2.99 (2H, m), 3.08(4H, m), 3.46 (4H, m), 3.59 (2H, m), 7.23–7.25 (1H, m), 7.74(2H, m).

Reference Example 1247-(5-Chloropentanoyl)-N-ethyl-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxamide

Ethyl isocyanate (781 μl) was added to a solution of5-chloro-1-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-1-pentanone (2.3 g)obtained in Reference Example 121 in tetrahydrofuran (30 ml). Afterstirring at room temperature for 60 minutes, water (50 g) was added,extracted with ethyl acetate, and washed with brine. The organic layerwas dried over anhydrous sodium sulfate, and the solvent was evaporatedunder reduced pressure to give a colorless solid (2.2 g).

¹H NMR (200 MHz, CDCl₃) δ 1.17 (3H, t, J=7.0 Hz), 1.89 (4H, m), 2.99(6H, m), 3.32 (2H, q, J=7.0 Hz), 3.56 (6H, m), 4.47 (1H, m), 7.19–7.23(1H, m), 7.71(2H, m).

Reference Example 1251-(2-Acetyl-1,2,3,4-tetrahydro-7-isoquinolinyl)-5-chloro-1-pentanone

Aluminum chloride (24 g, 181 mmol) was added by portions to a solutionof 2-acetyl-1,2,3,4-tetrahydroisoquinoline (15.0 g) obtained inReference Example 121 and 5-chlorovaleryl chloride (12.0 ml) in1,2-dichloroethane (50 ml) under ice-cooling. After stirring at roomtemperature for 30 minutes, the reaction mixture was poured into ice(500 g), extracted with ethyl acetate, and washed with brine. Theorganic layer was dried over anhydrous magnesium sulfate, and thesolvent was evaporated under reduced pressure to give a pale yellowsolid (14.2 g). Further recrystallization from ethanol-diethyl etherafforded the title compound as colorless crystals (12.5 g).

¹H NMR (200 MHz, DMSO-d₆) δ 1.76 (4H, m), 2.09 (3H, s), 2.86 (2H, t,J=5.8 Hz), 3.04 (2H, t, J=6.0 Hz), 3.67 (4H, m), 4.66 (2H, s), 7.30 (1H,s), 7.74(2H, m).

Reference Example 126 1,3-Dihydro-2,1,3-benzothiadiazole 2,2-dioxide

A solution of orthophenylenediamine (20 g) and sulfamide (20.4 g) indiglyme (200 ml) was stirred at 160° C. for 2 hours, the reactionmixture was cooled to room temperature, water (200 g) was pouredthereto, hydrochloric acid was added until pH 1, extracted with ethylacetate, and washed with 1N hydrochloric acid. The organic layer wasdried over anhydrous magnesium sulfate, and the solvent was evaporatedunder reduced pressure to give a reddish brown solid (14.2 g). Furtherrecrystallization from ethanol-diethyl ether afforded the title compoundas colorless crystals (13.2 g).

¹H NMR (300 MHz, DMSO-d₆) δ 6.77–6.91 (4H, m), 10.95 (2H, s).

Reference Example 127 1,3-Dimethyl-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide

Sodium hydride (5 g) was added to a solution of1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (10 g) obtained inReference Example 126 in dimethylformamide (100 ml), the mixture wasstirred at room temperature for 1 hour, methyl iodide was added, and themixture was stirred at room temperature for 18 hours. Water (200 g) waspoured into the reaction mixture, extracted with ethyl acetate, andwashed with brine. The organic layer was dried over anhydrous magnesiumsulfate, and the solvent was evaporated under reduced pressure to give areddish brown solid (9.9 g). Further recrystallization from water-ethylacetate afforded the title compound as colorless crystals (9.0 g).

¹H NMR (200 MHz, CDCl₃) δ 3.28 (6H, s), 6.74 (2H, q, J=3.2 Hz), 7.00(2H, q, J=3.4 Hz).

Reference Example 128

5-Chloro-1-(2,2-dioxide-1,3-dihydro-2,1,3-benzothiadiazol-5-yl)-1-pentanone

Using 1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide obtained inReference Example 126 and 5-chlorovaleryl chloride according to the samemethod as that of Reference Example 1, the title compound was obtainedas colorless crystals.

¹H NMR (200 MHz, CDCl₃) δ 1.75 (4H, m), 3.03 (2H, t, J=6.6 Hz), 3.68(2H, t, J=6.2 Hz), 6.89 (1H, d, J=8.4 Hz), 7.33 (1H, s), 7.62 (1H, d,J=8.4 Hz), 11.54 (2H, br).

Reference Example 1295-Chloro-1-(1,3-dimethyl-2,2-dioxide-1,3-dihydro-2,1,3-benzothiadiazol-5-yl)-1-pentanone

Using 1,3-dimethyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxideobtained in Reference Example 127 and 5-chlorovaleryl chloride accordingto the same method as that of Reference Example 1, the title compoundwas obtained as colorless crystals.

¹H NMR (200 MHz, CDCl₃) δ 1.89 (4H, m), 2.99 (2H, t, J=7.0 Hz), 3.35(6H, s), 3.60 (2H, t, J=6.2 Hz), 6.75 (1H, d, J=8.4 Hz), 7.39 (1H, s),7.69 (1H, d, J=8.4 Hz).

Reference Example 130 1,2,3,4-Tetrahydro-8-quinolineamine

A mixed solution of 8-nitroquinoline (25.0 g), platinum oxide (600 mg)and glacial acetic acid (300 ml) was stirred at room temperature for 4hours under the atmosphere of hydrogen at 5 atm. The reaction mixturewas filtered through Celite, and the solvent was evaporated underreduced pressure. Then, the solution was extracted with ethyl acetate,and washed with brine. The organic layer was dried over anhydrousmagnesium sulfate, the solvent was evaporated under reduced pressure,and purified by silica gel column chromatography to give the titlecompound as a reddish brown oil (15.2 g).

¹H NMR (200 MHz, CDCl₃) δ 1.96 (2H, quint, J=2.6 Hz), 2.76 (2H, t, J=6.2Hz), 3.56 (3H, br), 3.32 (2H, t, J=5.6 Hz), 6.53 (3H, m).

Reference Example 131 5,6-Dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one

A suspension of 1,1′-carbonyldiimidazole in tetrahydrofuran was added toa solution of 1,2,3,4-tetrahydro-8-quinolineamine (10 g) obtained inReference Example 130 in tetrahydrofuran (100 ml), and the mixture wasstirred at room temperature at 4 hours. The reaction mixture wasconcentrated to give a brown solid (11 g). Further recrystallizationfrom water-ethyl estate afforded the title compound as colorlesscrystals (10 g).

¹H NMR (200 MHz, CDCl₃) δ 2.00 (2H, t, J=5.4 Hz), 2.76 (2H, t, J=5.8Hz), 3.69 (2H, t, J=5.6 Hz), 6.80 (3H, m), 10.61 (1H, s).

Reference Example 1321-Methyl-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one

Sodium hydride (2.36 g) was added to a solution of5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (10 g) obtained inReference Example 131 in dimethylformamide (100 ml), the mixture wasstirred at room temperature for 1 hour, methyl iodide (3.68 ml) wasadded, and the mixture was stirred at room temperature for 18 hours.Water (200 g) was poured into the reaction mixture, extracted with ethylacetate, and washed with brine. The organic layer was dried overanhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure to give a pale yellow solid (9.7 g). Furtherrecrystallization from water-ethyl acetate afforded the title compoundas colorless crystals (9.0 g).

¹H NMR (200 MHz, CDCl₃) δ 2.12 (2H, quint, J=6.4 Hz), 2.86 (2H, t, J=6.2Hz), 3.41 (3H, s), 3.87 (2H, t, J=5.8 Hz), 6.79–7.04 (3H, m).

Reference Example 1338-(5-Chloropentanoyl)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one

Using 5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one obtained inReference Example 131 and 5-chlorovaleryl chloride according to the samemethod as that of Reference Example 1, the title compound was obtainedas colorless crystals.

¹H NMR (200 MHz, DMSO-d₆) δ 1.75 (4H, m), 2.00 (2H, m), 2.81 (2H, m),3.06 (2H, m), 3.72 (4H, m), 6.91 (1H, m), 7.65 (1H, m), 10.92 (1H, s).

Reference Example 1348-(5-Chloropentanoyl)-1-methyl-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one

Using 1-methyl-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-oneobtained in Reference Example 132 and 5-chlorovaleryl chloride accordingto the same method as that of Reference Example 1, the title compoundwas obtained as colorless crystals.

¹H NMR (200 MHz, CDCl₃) δ 1.85–1.93 (4H, m), 2.09 (2H, m), 2.88 (1H, m),3.00 (2H, m), 3.23 (1H, m), 3.45 (3H, s), 3.59 (2H, m), 3.86 (2H, m),6.87 (1H, t, J=8.4 Hz), 7.62 (1H, t, J=8.4 Hz).

Reference Example 1354-(1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-4-oxobutanoicacid

Aluminum chloride (62 g, 462 mmol) was added by portions to a mixture of1,3-dimethyl-1,3-dihydro-2H-benzimidazol-2-one (25 g, 154 mmol) obtainedin Reference Example 10 and succinic acid anhydride (15.4 g, 154 mmol)in dichloroethane. After stirring at room temperature for 30 minutes,the reaction mixture was poured into ice (500 g), extracted with ethylacetate, and washed with brine. The organic layer was dried overanhydrous magnesium sulfate, the solvent was evaporated under reducedpressure, and the residue was crystallized from ethanol-diethyl ether togive the title compound as colorless crystals (25.0 g).

¹H NMR (200 MHz, DMSO-d₆) δ 2.59 (2H, t, J=6.4 Hz), 3.28 (2H, t, J=6.2Hz), 3.36 (3H, s), 3.38 (3H, s), 7.24 (1H, d, J=8.4 Hz), 7.73 (1H, s),7.78 (1H, d, J=8.4 Hz), 12.01 (1H, br)

Reference Example 1364-(1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)butanoic acid

A solution of4-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-4-oxobutanoicacid (25 g, 101 mmol) obtained in Reference Example 135, 10% palladiumcarbon (2 g) and concentrated hydrochloric acid (3 ml) in acetic acidwas stirred at room temperature for 5 hours under the atmosphere ofhydrogen at 5 atm, and the reaction mixture was filtered through Celiteto remove palladium carbon. The solvent was evaporated under reducedpressure, and the residue was crystallized from ethanol-diethyl ether togive the title compound as colorless crystals (20.0 g).

¹H NMR (200 MHz, DMSO-d₆) δ 1.81 (2H, quint, J=7.0 Hz), 2.22 (2H, t,J=7.4 Hz), 2.63 (2H, t, J=7.4 Hz), 3.30 (3H, s), 3.31 (3H, s), 6.86–7.05(3H, m), 12.01 (1H, br).

Reference Example 1371,3-Dimethyl-3,6,7,8-tetrahydro-1H-naphtho[2,3-d]imidazole-2,5-dione

Oxalyl chloride (7.0 ml, 81 mmol) was added by portions. to a solutionof 4-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)butanoic acid(20 g, 81 mmol) obtained in Reference Example 136 and dimethylformamide(1 ml) in tetrahydrofuran under ice-cooling. After stirring at roomtemperature for 30 minutes, the reaction mixture was concentrated, thereaction residue was dissolved in nitroethane, and aluminum chloride(21.6 g, 162 mmol) was added by portions under ice-cooling. Afterstirring at room temperature for 30 minutes, the reaction mixture waspoured into ice (500 g), extracted with ethyl acetate, and washed withbrine. The organic layer was dried over anhydrous magnesium sulfate, thesolvent was evaporated under reduced pressure, and the residue wascrystallized from ethanol-diethyl ether to give the title compound ascolorless crystals (18.0 g).

¹H NMR (200 MHz, DMSO-d₆) δ 2.15 (2H, quint, J=6.6 Hz), 2.67 (2H, t,J=7.4 Hz), 3.02 (2H, t, J=7.4 Hz), 3.43 (3H, s), 3.44 (3H, s), 6.79 (1H,s), 7.67 (1H, s).

Reference Example 138 Ethyl(±)-1,3-dimethyl-2,5-dioxo-2,3,5,6,7,8-hexahydro-1H-naphtho[2,3-d]imidazole-6-carboxylate

60% Oily sodium hydride (6 g) was washed with n-hexane (2×30 ml), andthe solvent was removed by decantation. Tetrahydrofuran (200 ml) andsubsequently diethyl carbonate (9.8 g) were added thereto, and themixture was refluxed gently. To the suspension was added dropwise asolution of1,3-dimethyl-3,6,7,8-tetrahydro-1H-naphtho[2,3-d]imidazole-2,5-dione (10g, 43.4 mmol) obtained in Reference Example 137 in hot tetrahydrofuranwhile maintaining refluxing. The mixture was refluxed for 18 hours, andallowed to cool, and then acetic acid (18 ml) was carefully addeddropwise to decompose excessive sodium hydride. Further, water wasadded, extracted with ethyl acetate, and washed with brine. The organiclayer was dried over anhydrous magnesium sulfate, the solvent wasevaporated under reduced pressure, and the residue was crystallized fromethanol-diethyl ether to give the title compound as colorless crystals(7.0 g).

¹H NMR (200 MHz, DMSO-d₆) δ 1.21 (3H, t, J=6.8 Hz), 2.27 (2H, quint,J=6.6 Hz), 3.02 (2H, m), 3.31 (3H, s), 3.33 (3H, s), 3.72 (1H, dd,J=9.6, 5.8 Hz), 4.15 (2H, q, J=7.0 Hz), 7.09 (1H, s), 7.55 (1H, s).

Reference Example 139 Ethyl(±)-6-(3-chloropropyl)-1,3-dimethyl-2,5-dioxo-2,3,5,6,7,8-hexahydro-1H-naphtho[2,3-d]imidazole-6-carboxylate

60% Oily sodium hydride (832 mg) was added to a solution of ethyl(±)-1,3-dimethyl-2,5-dioxo-2,3,5,6,7,8-hexahydro-1H-naphtho[2,3-d]imidazole-6-carboxylate(5.0 g) obtained in Reference Example 138 in dimethylformamide,and themixture was stirred at 60° C. for 1 hour. 1-Bromo-3-chloropropane wasadded thereto, and the mixture was stirred at 60° C. for 4 hours. Thereaction mixture was allowed to cool, and water was added to decomposeexcessive sodium hydride. Then, the mixture was extracted with ethylacetate, and washed with brine. The organic layer was dried overanhydrous magnesium sulfate, the solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound as a pale yellow oil.

MS m/z: 379 [M+H]⁺

Reference Example 140 Ethyl(±)-6-(4-chlorobutyl)-1,3-dimethyl-2,5-dioxo-2,3,5,6,7,8-hexahydro-1H-naphtho[2,3-d]imidazole-6-carboxylate

Using ethyl(±)-1,3-dimethyl-2,5-dioxo-2,3,5,6,7,8-hexahydro-1H-naphtho[2,3-d]imidazole-6-carboxylateobtained in Reference Example 138 and 1-bromo-4-chlorobutane accordingto the same method as that of Reference Example 139, the title compoundwas obtained as a pale yellow oil.

MS m/z: 393 [M+H]⁺

Reference Example 141(±)-6-(3-Chloropropyl)-1,3-dimethyl-3,6,7,8-tetrahydro-1H-naphtho[2,3-d]imidazole-2,5-dione

A solution of ethyl(±)-6-(3-chloropropyl)-1,3-dimethyl-2,5-dioxo-2,3,5,6,7,8-hexahydro-1H-naphtho[2,3-d]imidazole-6-carboxylateobtained in Reference Example 139 in concentrated hydrochloric acid (130ml) was refluxed at 130° C. for 3 hours. The reaction mixture wasallowed to cool, neutralized with potassium carbonate, extracted withethyl acetate, and washed with brine. The organic layer was dried overanhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure to give the title compound as a pale yellow oil.

MS m/z: 307 [M+H]⁺

Reference Example 142(±)-6-(4-Chlorobutyl)-1,3-dimethyl-3,6,7,8-tetrahydro-1H-naphtho[2,3-d]imidazole-2,5-dione

Using ethyl(±)-6-(4-chlorobutyl)-1,3-dimethyl-2,5-dioxo-2,3,5,6,7,8-hexahydro-1H-naphtho[2,3-d]imidazole-6-carboxylateobtained in Reference Example 140 according to the same method as thatof Reference Example 141, the title compound was obtained as a paleyellow oil.

MS m/z: 321 [M+H]⁺

Reference Example 143 Ethyl (±)-5,6-dimethoxy-1-oxo-2-indanecarboxylate

Using 5,6-dimethoxy-1-indanone according to the same method as that ofReference Example 138, the title compound was obtained as pale yellowcrystals having a melting point of 140 to 141° C.

¹H NMR (200 MHz, CDCl₃) δ 1.32 (3H, t, J=6.8 Hz), 3.27 (1H, dd, J=17.2,8.0 Hz), 3.45 (1H, dd, J=17.2, 3.6 Hz), 3.70 (1H, q, J=3.6 Hz), 3.91(3H, s), 3.99 (3H, s), 4.27 (2H, q, J=6.8 Hz), 6.92 (1H, s), 7.18 (1H,s).

Reference Example 144 Ethyl(±)-2-(3-chloropropyl)-5,6-dimethoxy-1-oxo-2-indanecarboxylate

Using ethyl (±)-5,6-dimethoxy-1-oxo-2-indanecarboxylate obtained inReference Example 143 according to the same method as that of ReferenceExample 139, the title compound was obtained as a pale yellow oil.

¹H NMR (200 MHz, CDCl₃) δ 1.22 (3H, t, J=6.8 Hz), 1.73 (2H, m), 2.00(1H, m), 2.24 (1H, m), 2.98 (1H, d, J=17.2 Hz), 3.38 (1H, t, J=6.6 Hz),3.54 (1H, t, J=6.6 Hz), 3.61 (1H, d, J=17.2 Hz), 3.91 (3H, s), 3.99 (3H,s), 4.17 (2H, q, J=6.8 Hz), 6.90 (1H, s), 7.16 (1H, s).

Reference Example 145 Ethyl(±)-2-(3-chlorobutyl)-5,6-dimethoxy-1-oxo-2-indanecarboxylate

Using ethyl (±)-5,6-dimethoxy-1-oxo-2-indanecarboxylate obtained inReference Example 143 and 1-bromo-4-chlorobutane according to the samemethod as that of Reference Example 139, the title compound was obtainedas a pale yellow oil.

¹H NMR (200 MHz, CDCl₃) δ 1.23 (3H, t, J=7.6 Hz), 1.30–1.46 (2H, m),1.75–1.94 (3H, m), 2.14 (1H, m), 3.00 (1H, d, J=17.2 Hz), 3.39 (1H, t,J=6.6 Hz), 3.51 (1H, t, J=6.6 Hz), 3.62 (1H, d, J=17.2 Hz), 3.91 (3H,s), 3.99 (3H, s), 4.18 (2H, q, J=7.6 Hz), 6.91 (1H, s), 7.17 (1H, s).

Reference Example 146 (±)-2-(3-Chloropropyl)-5,6-dimethoxy-1-indanone

Using ethyl(±)-2-(3-chloropropyl)-5,6-dimethoxy-1-oxo-2-indanecarboxylate obtainedin Reference Example 144 according to the same method as that ofReference Example 141, the title compound was obtained as colorlesscrystals.

¹H NMR (200 MHz, CDCl₃) δ 1.65 (2H, m), 1.95 (2H, m), 2.65–2.77 (2H, m),3.29 (1H, dd, J=17.1, 7.8 Hz), 3.59 (2H, m), 3.91 (3H, s), 3.97 (3H, s),6.87 (1H, s), 7.16 (1H, s).

Reference Example 147 (±)-2-(4-Chlorobutyl)-5,6-dimethoxy-1-indanone

Using ethyl(±)-2-(3-chlorobutyl)-5,6-dimethoxy-1-oxo-2-indanecarboxylate obtainedin Reference Example 145 according to the same method as that ofReference Example 141, the title compound was obtained as colorlesscrystals.

¹H NMR (200 MHz, CDCl₃) δ 1.42–1.98 (6H, m), 2.62–2.79 (2H, m), 3.28(1H, dd, J=17.2, 7.4 Hz), 3.56 (2H, t, J=6.6 Hz), 3.91 (3H, s), 3.97(3H, s), 6.88 (1H, s), 7.18 (1H, s).

Reference Example 148 tert-Butyl2-(2-chlorophenyl)ethyl[5-(2,2-dioxide-1,3-dihydro-2,1,3-benzothiazol-5-yl)-5-oxopentyl]carbamate

Using5-chloro-1-(2,2-dioxide-1,3-dihydro-2,1,3-benzothiadiazol-5-yl)-1-pentanoneobtained in Reference Example 128 and 2-(2-chlorophenyl)ethylamineaccording to the same method as that of Reference Example 19, the titlecompound was obtained as a pale yellow oil.

MS m/z: 508 [M+H]⁺

Reference Example 149 tert-Butyl2-(2-chlorophenyl)ethyl[5-(1,3-dimethyl-2,2-dioxide-1,3-dihydro-2,1,3-benzothiadiazol-5-yl)-5-oxopentyl]carbamate

Using5-chloro-1-(1,3-dimethyl-2,2-dioxide-1,3-dihydro-2,1,3-benzothiadiazol-5-yl)-1-pentanoneobtained in Reference Example 129 and 2-(2-chlorophenyl)ethylamineaccording to the same method as that of Reference Example 19, the titlecompound was obtained as a pale yellow oil.

¹H NMR (200 MHz, CDCl₃) δ 1.41 (9H, s), 1.42–1.64 (4H, m), 2.97 (4H, m),3.25 (2H, m), 3.34 (3H, s), 3.35 (3H, s), 3.45 (2H, m), 6.74 (1H, d,J=8.4 Hz), 7.18–7.39 (5H, m), 7.67 (1H, d, J=8.4 Hz).

Reference Example 150 tert-Butyl(±)-2-(2-chlorophenyl)ethyl[3-(1,3-dimethyl-2,5-dioxo-2,3,5,6,7,8-hexahydro-1H-naphtho[2,3-d]imidazol-6-yl)propyl]carbamate

Using(±)-6-(3-chloropropyl)-1,3-dimethyl-3,6,7,8-tetrahydro-1H-naphtho[2,3-d]imidazole-2,5-dioneobtained in Reference Example 141 and 2-(2-chlorophenyl)ethylamineaccording to the same method as that of Reference Example 19, the titlecompound was obtained as a pale yellow oil.

¹H NMR (200 MHz, CDCl₃) δ 1.38 (9H, m), 1.42–1.61 (4H, m), 1.87 (2H, m),2.23 (1H, m), 2.93–3.12 (4H, m), 3.19 (2H, m), 3.32 (2H, m), 3.34 (3H,s), 3.36 (3H, s), 6.72 (1H, s), 7.11–7.30 (4H, m), 7.60 (1H, s).

Reference Example 151 tert-Butyl2-(1H-indol-3-yl)ethyl[5-oxo-5-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)pentyl]carbamate

Using8-(5-chloropentanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(1.00 g) obtained in Reference Example 1 and tryptamine (548 mg)according to the same method as that of Reference Example 19, the titlecompound (822 mg) was obtained as pale yellow amorphous powders.

¹H NMR (300 MHz, CDCl₃) δ 1.30–1.80 (13H, m), 2.70 (2H, t, J=7.8 Hz),2.80–3.05 (6H, m), 3.10–3.35 (4H, m), 3.40–3.55 (2H, m), 4.12 (2H, t,J=8.4 Hz), 6.95–7.25 (3H, m), 7.36 (1H, d, J=7.8 Hz), 7.60–7.75 (3H, m),8.10–8.30 (1H, br).

Reference Example 152 tert-Butyl(±)-2-hydroxy-2-phenylethyl[5-oxo-5-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)pentyl]carbamate

Using8-(5-chloropentanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(1.00 g) obtained in Reference Example 1 and (±)-2-amino-1-phenylethanol(470 mg) according to the same method as that of Reference Example 19,the title compound (1.29 g) was obtained as a pale yellow oil.

¹H NMR (200 MHz, CDCl₃) δ 1.47 (9H, s), 1.50–1.90 (4H, m), 2.60–3.50(13H, m), 4.00–4.20 (2H, m), 4.70–5.00 (1H, m), 7.10–7.45 (5H, m), 7.66(1H, s), 7.70 (1H, s).

Reference Example 153 tert-Butyl(±)-2-hydroxy-2-(3-hydroxyphenyl)ethyl[5-oxo-5-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)pentyl]carbamate

Using8-(5-chloropentanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(1.00 g) obtained in Reference Example 1 and (±)-norphenylephrinehydrochloride (650 mg) according to the same method as that of ReferenceExample 82, the title compound (201 mg) was obtained as pale yellowamorphous powders.

¹H NMR (300 MHz, CDCl₃) δ 1.40–1.80 (4H, m), 1.47 (9H, s), 2.71 (2H, t,J=7.8 Hz), 2.91 (2H, t, J=7.2 Hz), 3.01 (2H, t, J=7.8 Hz), 3.05–3.60(7H, m), 4.13 (2H, t, J=8.4 Hz), 4.60–4.90 (1H, m), 6.35–6.60 (1H, br),6.75 (1H, d, J=8.5 Hz), 6.80–6.90 (2H, m), 7.18 (1H, t, J=7.8 Hz), 7.66(1H, s), 7.70 (1H, s)

Reference Example 1546-(5-Chloropentanoyl)-1-methyl-3,4-dihydro-2(1H)-quinolinone

Using 1-methyl-3,4-dihydro-2(1H)-quinolinone (1.3 g) and 3-chlorovalerylchloride (1.49 g) according to the same method as that of ReferenceExample 1, the title compound was obtained as colorless crystals (930mg) having a melting point of 62 to 63° C.

¹H NMR (400 MHz, CDCl₃) δ 1.84–1.94 (4H, m), 2.69 (2H, t, J=8 Hz),2.96–3.00 (4H, m), 3.39 (3H, s), 3.59 (2H, t, J=6 Hz), 7.04 (1H, d,J=8.3 Hz), 7.79 (1H, d, J=1.5 Hz), 7.88 (1H, dd, J=8.3, 1.5 Hz). IR(KBr) νcm⁻¹: 1669, 1601, 1504, 1426, 1351, 1304, 1205, 1123.

Reference Example 155 tert-Butyl2-(2-chloro-4-fluorophenyl)ethyl[5-oxo-5-(2-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)pentyl]carbamate

Using8-(5-chloropentanoyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-one(438 mg) obtained in Reference Example 3 and(2-(2-chloro-4-fluorophenyl)ethylamine (573 mg) according to the samemethod as that of Reference Example 19, the title compound (452 mg) wasobtained as a pale yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 1.42 (9H, s), 1.51–1.75 (4H, m), 2.01–2.08(2H, m), 2.82 (2H, t, J=6 Hz), 2.85–2.98 (4H, m), 3.13–3.21 (2H, m),3.38 (2H, t, J=7 Hz), 3.54 (2H, s), 3.74 (2H, t, J=6 Hz), 6.91 (1H, dt,J=2.7, 8.0 Hz), 7.08–7.25 (2H, m), 7.72 (2H, s).

Reference Example 156 tert-Butyl5-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-5-oxopentyl[2-(2-chloro-4-fluorophenyl)ethyl]carbamate

Using 1-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-5-chloropentan-1-one (420mg) obtained in Reference Example 11 and2-(2-chloro-4-fluorophenyl)ethylamine (573 mg) according to the samemethod as that of Reference Example 19, the title compound (554 mg) wasobtained as a pale yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 1.41 (9H, s), 1.51–1.73 (4H, m), 2.25 (3H, s),2.94 (4H, br.s,), 3.13–3.25 (4H, m), 3.38 (2H, t, J=7 Hz), 4.11 (2H, t,J=7 Hz), 6.91 (1H, dt, J=2.5, 7.8 Hz), 7.08–7.24 (2H, m), 7.80 (1H, s),7.81 (1H, d, J=8.0 Hz), 8.23 (1H, d, J=8.0 Hz).

Reference Example 157 tert-Butyl2-(2-chloro-4-fluorophenyl)ethyl[5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-5-oxopentyl]carbamate

Using 6-(5-chloropentanoyl)-1-methyl-3,4-dihydroquinolin-2(1H)-one (420mg) obtained in Reference Example 154 and2-(2-chloro-4-fluorophenyl)ethylamine (573 mg) according to the samemethod as that of Reference Example 19, the title compound (472 mg) wasobtained as a pale yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 1.42 (9H, s), 1.51–1.73 (4H, m), 2.68 (2H, t,J=7.0 Hz), 2.95–2.99 (6H, m), 3.13–3.21 (2H, m), 3.36–3.40 (2H, m), 3.39(3H, s), 6.91 (1H, dt, J=2.5, 8.3 Hz), 7.02 (1H, d, J=8.3 Hz), 7.09–7.22(2H, m), 7.78 (1H, s), 7.87 (1H, d, J=8.3 Hz).

Reference Example 158 tert-Butyl5-oxo-5-(2-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)pentyl{2-[2-(trifluoromethoxy)phenyl]ethyl}carbamate

Using8-(5-chloropentanoyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-one(292 mg) obtained in Reference Example 3 and2-[2-(trifluoromethoxy)phenyl]ethylamine (451 mg) according to the samemethod as that of Reference Example 19, the title compound (205 mg) wasobtained as a pale yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 1.42 (9H, s), 1.51–1.72 (4H, m), 2.02–2.34(2H, m), 2.80–2.90 (6H, m), 3.13–3.20 (2H, m), 3.38 (2H, br.s), 3.54(2H, s), 3.72–3.75 (2H, m), 7.22 (4H, br.s), 7.72 (2H, s).

Reference Example 159 tert-Butyl5-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-5-oxopentyl{2-[2-(trifluoromethoxy)phenyl]ethyl}carbamate

Using 1-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-5-chloropentan-1-one (280mg) obtained in Reference Example 11 and2-[2-(trifluoromethoxy)phenyl]ethylamine (451 mg) according to the samemethod as that of Reference Example 19, the title compound (457 mg) wasobtained as a pale yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 1.42 (9H, s), 1.51–1.69 (4H, m), 2.25 (3H, s),2.92–2.99 (4H, m), 3.12–3.25 (4H, m), 3.38 (2H, br.s), 4.09–4.15 (2H,m), 7.19–7.32 (4H, m), 7.80 (1H, s), 7.82 (1H, d, J=8.3 Hz), 8.23 (1H,d, J=8.3 Hz).

Reference Example 160 tert-Butyl5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-5-oxopentyl{2-[2-(trifluoromethoxy)phenyl]ethyl}carbamate

Using 6-(5-chloropentanoyl)-1-methyl-3,4-dihydroquinolin-2(1H)-one (280mg) obtained in Reference Example 154 and2-[2-(trifluoromethoxy)phenyl]ethylamine (451 mg) according to the samemethod as that of Reference Example 19, the title compound (442 mg) wasobtained as a pale yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 1.42 (9H, s), 1.51–1.73 (4H, m), 2.68 (2H, t,J=7.7 Hz), 2.88–3.00 (6H, m), 3.14–3.21 (2H, m), 3.35–3.42 (2H, m), 3.39(3H, s), 7.02 (1H, d, J=8.3 Hz), 7.09–7.22 (2H, m), 7.78 (1H, s), 7.87(1H, d, J=8.3 Hz).

Reference Example 161 tert-Butyl5-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-5-oxopentyl{2-[2-(trifluoromethoxy)phenyl]ethyl}carbamate

Using5-(5-chloropentanoyl)-1,3-dimethyl-1,3-dihydro-2H-benzimidazol-2-one(281 mg) obtained in Reference Example 10 and2-[2-(trifluoromethoxy)phenyl]ethylamine (451 mg) according to the samemethod as that of Reference Example 19, the title compound (244 mg) wasobtained as a pale yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 1.42 (9H, s), 1.51–1.78 (4H, m), 2.89 (2H,br.s), 3.01 (2H, br.s), 3.15–3.23 (2H, m), 3.38 (2H, br.s), 3.46 (6H,s), 6.98 (1H, d, J=8.0 Hz), 7.23–7.30 (4H, m), 7.63 (1H, s), 7.78 (1H,d, J=8.0 Hz).

Reference Example 162 tert-Butyl3-(2-methoxyphenyl)propyl[5-oxo-5-(2-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)pentyl]carbamate

Using8-(5-chloropentanoyl)-5–6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-one(292 mg) obtained in Reference Example 3 and3-(2-methoxyphenyl)propylamine (364 mg) according to the same method asthat of Reference Example 19, the title compound (165 mg) was obtainedas a pale yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 1.43 (9H, s), 1.60 (2H, br.s), 1.67–1.74 (2H,m), 1.76–1.84 (2H, m), 2.00–2.06 (2H, m), 2.58 (2H, t, J=7.5 Hz), 2.82(2H, t, J=6.0 Hz), 2.94 (2H, t, J=7.0 Hz), 3.22 (4H, br.s), 3.54 (2H,s), 3.74 (2H, t, J=6.0 Hz), 3.81 (3H, s), 6.84 (1H, d, J=8.3 Hz), 6.87(1H, t, J=7.5 Hz), 7.12 (1H, d, J=7.5 Hz), 7.17 (1H, t, J=7.5 Hz), 7.73(2H, s).

Reference Example 163 tert-Butyl5-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-5-oxopentyl[3-(2-methoxyphenyl)propyl]carbamate

Using 1-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-5-chloropentan-1-one (280mg) obtained in Reference Example 11 and 3-(2-methoxyphenyl)propylamine(364 mg) according to the same method as that of Reference Example 19,the title compound (417 mg) was obtained as a pale yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 1.44 (9H, s), 1.60 (2H, br.s), 1.67–1.72 (2H,m), 1.76–1.84 (2H, m), 2.25 (3H, s), 2.58 (2H, t, J=7.3 Hz), 2.93–2.96(2H, m), 3.23 (6H, br.s), 3.81 (3H, s), 4.09–4.15 (2H, m), 6.83 (1H, d,J=8.3 Hz), 6.87 (1H, t, J=7.3 Hz), 7.12 (1H, d, J=7.3 Hz), 7.17 (1H, t,J=7.3 Hz), 7.81 (1H, s), 7.82 (1H, d, J=8.1 Hz), 8.23 (1H, d, J=8.1 Hz).

Reference Example 164 tert-Butyl3-(2-methoxyphenyl)propyl[5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-5-oxopentyl]carbamate

Using 6-(5-chloropentanoyl)-1-methyl-3,4-dihydroquinolin-2(1H)-one (280mg) obtained in Reference Example 154 and 3-(2-methoxyphenyl)propylamine(364 mg) according to the same method as that of Reference Example 19,the title compound (415 mg) was obtained as a pale yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 1.44 (9H, s), 1.61 (2H, br.s), 1.68–1.75 (2H,m), 1.77–1.84 (2H, m), 2.58 (2H, t, J=7.8 Hz), 2.68 (2H, t, J=7.8 Hz),2.95–2.98 (4H, m), 3.21 (4H, br.s), 3.39 (3H, s), 3.81 (3H, s), 6.84(1H, d, J=8.0 Hz), 6.88 (1H, t, J=7.3 Hz), 7.01 (1H, d, J=8.3 Hz), 7.12(1H, d, J=7.3 Hz), 7.17 (1H, t, J=7.3 Hz), 7.79 (1H, s), 7.87 (1H, d,J=8.3 Hz).

Reference Example 165 tert-Butyl5-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-5-oxopentyl[3-(2-methoxyphenyl)propyl]carbamate

Using5-(5-chloropentanoyl)-1,3-dimethyl-1,3-dihydro-2H-benzimidazol-2-one(281 mg) obtained in Reference Example 10 and3-(2-methoxyphenyl)propylamine (364 mg) according to the same method asthat of Reference Example 19, that title compound (387 mg) was obtainedas a pale yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 1.44 (9H, s), 1.63 (2H, br.s), 1.70–1.85 (4H,m), 2.58 (2H, t, J=7.8 Hz), 3.01 (2H, t, J=7.0 Hz), 3.25 (4H, br.s),3.46 (6H, s), 3.81 (3H, s), 6.84 (1H, d, J=8.0 Hz), 6.87 (1H, t, J=7.3Hz), 6.98 (1H, d, J=8.0 Hz), 7.12 (1H, d, J=7.3 Hz), 7.17 (1H, t, J=7.3Hz), 7.63 (1H, s), 7.78 (1H, d, J=8.0 Hz).

Reference Example 166 tert-Butyl2-(2-ethoxyphenoxy)ethyl[5-oxo-5-(2-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)pentyl]carbamate

Using8-(5-chloropentanoyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-one(292 mg) obtained in Reference Example 3 and2-(2-ethoxyphenoxy)ethylamine (399 mg) according to the same method asthat of Reference, Example 19, the title compound (211 mg) was obtainedas a pale yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 1.42 (3H, t, J=7 Hz), 1.45 (9H, s), 1.61–1.75(4H, m), 2.00–2.06 (2H, m), 2.81 (2H, t, J=6 Hz), 2.94 (2H, br.d, J=6.6Hz), 3.42 (2H, t, J=7.3 Hz), 3.54 (2H, s), 3.59–3.63 (2H, m), 3.74 (2H,t, J=6 Hz), 4.03–4.08 (2H, m), 4.12 (2H, q, J=7 Hz), 6.89 (4H, br.s),7.73 (2H, s).

Reference Example 167 tert-Butyl5-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-5-oxopentyl[2-(2-ethoxyphenoxy)ethyl]carbamate

Using 1-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-5-chloropentan-1-one (280mg) obtained in Reference Example 11 and 2-(2-ethoxyphenoxy)ethylamine(399 mg) according to the same method as that of Reference Example-19,the title compound (398 mg) was obtained as a pale yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 1.41 (3H, t, J=7 Hz), 1.45 (9H, s), 1.61–1.72;(4H, m), 2.25 (3H, s), 2.95–2.97 (2H, m), 3.22 (2H, t, J=8 Hz), 3.42(2H, t, J=7 Hz), 3.58–3.68 (2H, m), 4.03–4.06 (2H, m), 4.11 (4H, q, J=7Hz), 6.89 (4H, br.s), 7.79 (1H, s), 7.82 (1H, d, J=8.3 Hz), 8.22 (1H, d,J=8.3 Hz).

Reference Example 168 tert-Butyl2-(2-ethoxyphenoxy)ethyl[5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-5-oxopentyl]carbamate

Using 6-(5-chloropentanoyl)-1-methyl-3,4-dihydroquinolin-2(1H)-one (280mg) obtained in Reference Example 154 and 2-(2-ethoxyphenoxy)ethylamine(399 mg) according to the same method as that of Reference Example 19,the title compound (425 mg) was obtained as a pale yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 1.43 (3H, t, J=7 Hz), 1.45 (9H, s), 1.70–1.76(4H, m), 2.68 (2H, t, J=8.3 Hz), 2.94–2.98 (4H, m), 3.39 (3H, s), 3.43(2H, t, J=7.3 Hz), 3.59–3.64 (2H, m), 4.03–4.08 (2H, m), 4.12 (2H, q,J=7 Hz), 6.89 (4H, br.s), 7.01 (1H, d, J=8.3 Hz), 7.78 (1H, s), 7.88(1H, d, J=8.3 Hz).

Reference Example 169 tert-Butyl5-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-5-oxopentyl[2-(2-ethoxyphenoxy)ethyl]carbamate

Using5-(5-chloropentanoyl)-1,3-dimethyl-1,3-dihydro-2H-benzimidazol-2-one(281 mg) obtained in Reference Example 10 and2-(2-ethoxyphenoxy)ethylamine (399 mg) according to the same method asthat of Reference Example 19, the title compound (368 mg) was obtainedas a pale yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 1.42 (3H, t, J=6.7 Hz), 1.45 (9H, s),1.70–1.78 (4H, m), 3.01–3.06 (2H, m), 3.42–3.46 (2H, m), 3.46 (6H, s),3.59–3.64 (2H, m), 4.05 (2H, q, J=6.7 Hz), 4.10–4.15 (2H, m), 6.89 (4H,br.s), 6.97 (1H, d, J=8 Hz), 7.63 (1H, s), 7.78 (1H, d, J=8 Hz).

Reference Example 170 tert-Butyl2-[(2-ethoxyphenyl)amino]ethyl[5-oxo-5-(2-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)pentyl]carbamate

Using8-(5-chloropentanoyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-one(584 mg) obtained in Reference Example 3 andN-(2-ethoxyphenyl)ethane-1,2-diamine (793 mg) according to the samemethod as that of Reference Example 19, the title compound (611 mg) wasobtained as a pale yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 1.42 (3H, t, J=7.0 Hz), 1.47 (9H, s), 1.63(1H, br.s), 1.66–1.75 (4H, m), 2.00–2.06 (2H, m), 2.82 (2H, t, J=6.1Hz), 2.92–2.98 (2H, m), 3.23–3.33 (4H, m), 3.44 (2H, br.s), 3.54 (2H,s), 3.74 (2H, t, J=6.1 Hz), 4.05 (2H, br.s), 6.63 (2H, br.s), 6.74 (1H,d, J=7.6 Hz), 6.84 (1H, t, J=7.6 Hz), 7.72 (1H, s), 7.73 (1H, s).

Reference Example 171 tert-Butyl5-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-5-oxopentyl{2-[(2-ethoxyphenyl)amino]ethyl}carbamate

Using 1-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-5-chloropentan-1-one (560mg) obtained in Reference Example 11 andN-(2-ethoxyphenyl)ethane-1,2-diamine (793 mg) according to the samemethod as that of Reference Example 19, the title compound (695 mg) wasobtained as a pale yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 1.42 (3H, t, J=6.8 Hz), 1.47 (9H, s), 1.62(1H, br.s), 1.67–1.74 (4H, m), 2.26 (3H, s), 2.93–2.97 (2H, m),3.21–3.25 (4H, m), 3.31 (2H, t, J=6.8 Hz), 3.43 (2H, br.s), 4.04 (2H,br.s), 4.12 (2H, q, J=6.8 Hz), 6.63 (2H, br.s), 6.74 (1H, d, J=7.6 Hz),6.84 (1H, t, J=7.6 Hz), 7.80 (1H, s), 7.82 (1H, d, J=8.3 Hz), 8.23 (1H,d, J=8.3 Hz).

Reference Example 172 tert-Butyl5-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-5-oxopentyl{2-[(2-ethoxyphenyl)amino]ethyl}carbamate

Using5-(5-chloropentanoyl)-1,3-dimethyl-1,3-dihydro-2H-benzimidazol-2-one(562 mg) obtained in Reference Example 10 andN-(2-ethoxyphenyl)ethane-1,2-diamine (793 mg) according to the samemethod as that of Reference Example 19, the title compound (670 mg) wasobtained as a pale yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 1.42 (3H, t, J=6.8 Hz), 1.47 (9H, s), 1.63(1H, br.s), 1.71–1.80 (4H, m), 3.00–3.05 (2H, m), 3.27–3.33 (4H, m),3.42–3.49 (2H, m), 3.46 (6H, s), 4.04 (2H, br.s), 6.63 (2H, br.s), 6.74(1H, d, J=7.3 Hz), 6.84 (1H, t, J=7.3 Hz), 6.98 (1H, d, J=8.0 Hz), 7.62(1H, s), 7.78 (1H, d, J=8.0 Hz).

Reference Example 1738-[3-(1-Acetyl-4-piperidinyl)propanoyl]-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-one

Thionyl chloride (5.6 ml) was added dropwise to a suspension of3-(1-acetyl-4-piperidinyl)propanoic acid (13.8 g) in dichloromethane (50ml) under ice-cooling. After stirred at the same temperature for 30minutes, the mixture was concentrated under reduced pressure, 30 ml ofhexane was added to the residue, and precipitated crystals were filteredand dried. Aluminum chloride (28 g) was added by portions to asuspension of the resulting corresponding acid chloride and5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-one (10 g) in1,2-dichloroethane (50 ml) under ice-cooling. After stirred at roomtemperature for 30 minutes, the reaction mixture was poured into ice(200 g), extracted with ethyl acetate, and washed with brine. Theorganic layer was dried over anhydrous magnesium sulfate, the solventwas evaporated under reduced pressure, and the residue was crystallizedfrom ethanol-diethyl ether to give the title compound as pale yellowcrystals (8.0 g) having a melting point of 119 to 120° C.

¹H NMR (400 MHz, CDCl₃) δ 1.08–1.24 (2H, m), 1.55–1.81 (5H, m),2.00–2.10 (2H, m), 2.09 (3H, s), 2.53 (1H, d, t, J=2.5, 13 Hz), 2.83(2H, t, J=6.7 Hz), 2.95 (2H, t, J=7.5 Hz), 3.03 (1H, d, t, J=2.5, 13Hz), 3.56 (2H, s), 3.75 (2H, t, J=6.7 Hz), 3.80 (1H, d, J=7.5 Hz), 4.61(1H, d, J=7.5 Hz), 7.73 (2H, s). IR (KBr) νcm⁻¹: 1713, 1634, 1341, 1152.

Reference Example 1748-[3-(4-Piperidinyl)propanoyl]-5,4-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-one

Concentrated hydrochloric acid (150 ml) was added to8-[3-(1-acetyl-4-piperidinyl)propanoyl]-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-one(7.5 g) obtained in Reference Example 173, and the mixture was stirredat 120° C. for 5 hours. Hydrochloric acid was evaporated under reducedpressure, pH was adjusted to 12 with 1N aqueous sodium hydroxidesolution, and extracted with ethyl acetate (100 ml) three times. Theorganic layer was dried over anhydrous magnesium sulfate, and thesolvent was evaporated to give the title compound as pale yellowcrystals (3.48 g) having a melting point of 128 to 129° C.

¹H NMR (400 MHz, CDCl₃) δ 1.14 (1H, d, t, J=4, 12 Hz), 1.17 (1H, d, t,J=4, 12 Hz), 1.42–1.46 (1H, m), 1.65–1.81 (5H, m), 2.04 (2H, t, J=7 Hz),2.58 (2H, d, t, J=2, 12 Hz), 2.83 (2H, t, J=6 Hz), 2.94 (2H, t, J=7 Hz),3.07 (2H, br, d, J=12 Hz), 3.55 (2H, s), 3.74 (2H, t, J=6 Hz), 7.73 (2H,s). IR (KBr) νcm⁻¹: 1708, 1660, 1603, 1339, 1156.

Reference Example 1759-[3-(1-Acetyl-4-piperidinyl)propanoyl]-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-one

Using 3-(1-acetyl-4-piperidinyl)propanoic acid (13.8 g) and2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-one (10.8 g)according to the same method as that of Reference Example 172, the titlecompound was obtained as colorless crystals (15.5 g) having a meltingpoint of 130 to 131° C.

¹H NMR (400 MHz, CDCl₃) δ 1.09–1.28 (2H, m), 1.55–1.82 (5H, m),1.93–2.00 (2H, m), 2.09 (3H, s), 2.53 (1H, d, t, J=2.5, 12.7 Hz), 2.68(2H, t, J=7 Hz), 2.85 (2H, t, J=6 Hz), 2.93–2.98 (4H, m), 3.03 (1H, d,t, J=2.5, 12.7 Hz), 3.82 (1H, d, J=12.7 Hz), 3.90 (2H, t, J=6 Hz), 4.61(1H, d, J=13 Hz), 7.62 (2H, d, J=5 Hz). IR (KBr) νcm⁻¹: 1671, 1634,1360, 1160, 972.

Reference Example 1769-[3-(4-Piperidinyl)propanoyl]-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-one

Using9-[3-(1-acetyl-4-piperidinyl)propanoyl]-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-one(15 g) obtained in Reference Example 175 according to the same method asthat of Reference Example 173, the title compound was obtained as paleyellow crystals (8.9 g) having a melting point of 81 to 82° C.

¹H NMR (400 MHz, CDCl₃) δ 1.14 (1H, d, t, J=4, 12 Hz), 1.17 (1H, d, t,J=4, 12 Hz), 1.41–1.48 (1H, m), 1.65–1.70 (4H, m), 1.73 (1H, br. s),1.94–2.00 (2H, m), 2.58 (2H, d, t, J=2, 12 Hz), 2.68 (2H, t, J=6.7 Hz),2.84 (2H, t, J=6 Hz), 2.92–2.96 (4H,m), 3.07 (2H, br, d, J=12 Hz), 3.89(2H, t, J=6 Hz),7.62 (2H, d, J=5 Hz). IR (KBr) νcm⁻¹: 3442, 2905, 1673,1588, 1361, 1164.

Reference Example 1776-(5-Chloropentanoyl)-3,4-dihydro-2(1H)-quinazoline

Using 3,4-dihydro-2(1H)-quinazoline, (4.0 g) and 5-chlorovalerylchloride (8.37 g) according to the same method as that of ReferenceExample 1, the title compound was obtained as colorless crystals (3.9 g)

¹H NMR (200 MHz, DMSO-d₆) δ 1.73 (4H, m), 2.96 (2H, t, J=7.0 Hz), 3.67(2H, t, J=6.4 Hz), 4.38 (2H, s), 6.83 (1H, d, J=8.8 Hz), 7.01 (1H, s),7.75–7.80 (2H, m), 9.44 (1H, s). elementary analysis as C₁₃H₁₅ClN₂O₂calculation value: C, 58.54; H, 5.67; N, 10.50. experimental value: C,58.47; H, 5.51; N, 10.39. MS m/z: 267 [M+H]⁺

Reference Example 1786-(5-Chloropentanoyl)-1,3-dimethyl-3,4-dihydro-2(1H)-quinazoline

Using 1,3-dimethyl-3,4-dihydro-2(1H)-quinazoline (4.0 g) and5-chlorovaleryl chloride (6.46 g) according to the same method as thatof Reference Example 1, the title compound was obtained as colorlesscrystals (3.5 g).

¹H NMR (300 MHz, CDCl₃) δ 1.91–1.87 (4H, m), 2.99–2.94 (2H,m), 3.06 (3H,s) 3.35 (3H, s), 3.61–3.57 (2H, m), 4.43 (2H, s), 6.87 (1H, d, J=8.4Hz), 7.07 (1H, d, J=2.1 Hz), 7.88 (1H, d, J=8.4, 2.1 Hz).

Reference Example 1798-(4-Chlorobutanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one

Using 1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (20.0 g) and5-chlorovaleryl chloride (17.8 ml) according to the same method as thatof Reference Example 1, the title compound (23.0 g) was obtained ascolorless crystals having a melting point of 123 to 124° C.

¹H NMR (200 MHz, CDCl₃) δ 2.23 (2H, quintet, J=6.4 Hz), 2.72 (2H, t,J=7.6 Hz), 3.04 (2H, t, J=7.6 Hz), 3.13 (2H, t, J=6.4 Hz), 3.24 (2H, t,J=8.6 Hz), 3.68 (2H, t, J=6.4 Hz), 4.14 (2H, t, J=8.6 Hz), 7.70 (1H, s),7.75 (1H, s). elementary analysis as C₁₅H₁₆ClNO₂ calculation value: C,64.87; H, 5.81; N, 5.04. experimental value: C, 64.88; H, 5.72; N, 4.91.

Reference Example 180 tert-Butylbenzyl[4-oxo-4-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)butyl]carbamate

Using8-(4-chlorobutanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(1.00 g) obtained in Reference Example 179 and benzylamine (1.16 g)according to the same method as that of Reference Example 19, the titlecompound (526 mg) was obtained as a pale yellow oil.

¹H NMR (200 MHz, CDCl₃) δ 1.44 (9H, s), 1.80–2.05 (2H, m), 2.71 (2H, t,J=7.6 Hz), 2.80–2.95 (2H, m), 3.11 (2H, t, J=7.6 Hz), 3.15–3.40 (4H, m),4.13 (2H, t, J=8.8 Hz), 4.45 (2H, s), 7.20–7.40 (5H, m), 7.64 (1H, s),7.68 (1H, s).

Reference Example 181 tert-Butyl2-(2-methoxyphenyl)ethyl[4-oxo-4-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)butyl]carbamate

Using8-(4-chlorobutanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(1.00 g) obtained in Reference Example 179 and2-(2-methoxyphenyl)ethylamine (1.63 g) according to the same method asthat of Reference Example 19, the title compound (797 mg) was obtainedas a pale yellow oil.

¹H NMR (200 MHz, CDCl₃) δ 1.41 (9H, s), 1.85–2.00 (2H, m), 2.71 (2H, t,J=5.2 Hz), 2.75–2.95 (4H, m), 3.01 (2H, t, J=5.2 Hz), 3.15–3.45 (6H, m),3.83 (3H, s), 4.13 (2H, t, J=5.8 Hz), 6.80–6.90 (2H, m), 7.05–7.20 (2H,m), 7.66 (1H, s), 7.71 (1H, s).

Reference Example 182 tert-Butylbenzyl[5-oxo-5-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)pentyl]carbamate

Using8-(5-chloropentanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(500 mg) obtained in Reference Example 1 and benzylamine (550 mg)according to the same method as that of Reference Example 19, the titlecompound (498 mg) was obtained as a pale yellow oil.

¹H NMR (200 MHz, CDCl₃) δ 1.40–1.90 (4H, m), 1.45 (9H, s), 2.71 (2H, t,J=7.4 Hz), 2.80–3.35 (8H, m), 4.00–4.50 (4H, m), 7.15–7.40 (5H, m), 7.66(1H, s), 7.70 (1H, s).

Reference Example 183 tert-Butyl2-methoxybenzyl[5-oxo-5-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)pentyl]carbamate

Using8-(5-chloropentanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(500 mg) obtained in Reference Example 1 and 2-methoxybenzylamine (704mg) according to the same method as that of Reference Example 19, thetitle compound (524 mg) was obtained as a pale yellow oil.

¹H NMR (200 MHz, CDCl₃) δ 1.40–1.80 (4H, m), 1.41 (9H, s), 2.71 (2H, t,J=7.6 Hz), 2.80–3.40 (8H, m), 3.82 (3H, s), 4.00–4.50 (4H, m), 6.80–7.00(2H, m), 7.05–7.30 (2H, m), 7.67 (1H, s), 7.71 (1H, s).

Reference Example 184 tert-Butylbenzyl[6-oxo-6-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)hexyl]carbamate

Using8-(6-bromohexanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(700 mg) obtained in Reference Example 2 and benzylamine (643 mg)according to the same method as that of Reference Example 19, the titlecompound (554 mg) was obtained as a pale yellow oil.

¹H NMR (200 MHz, CDCl₃) δ 1.10–1.80 (6H, m), 1.45 (9H, s), 2.71 (2H, t,J=7.6 Hz), 2.68 (2H, t, J=7.6 Hz), 3.02 (2H, t, J=7.6 Hz), 3.10–3.30(4H, m), 4.13 (2H, t, J=8.8 Hz), 4.42 (2H, s), 7.15–7.40 (5H, m), 7.67(1H, s), 7.71 (1H, s).

Reference Example 185 tert-Butyl2-methoxybenzyl[6-oxo-6-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)hexyl]carbamate

Using8-(6-bromohexanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(600 mg) obtained in Reference Example 2 and 2-methoxybenzylamine (704mg) according to the same method as that of Reference Example 19, thetitle compound (486 mg) was obtained as a pale yellow oil.

¹H NMR (300 MHz, CDCl₃) δ 1.15–1.60 (4H, m), 1.42 (9H, s), 2.72 (2H,quintet, J=7.5 Hz), 2.71 (2H, t, J=7.5 Hz), 2.88 (2H, t, J=7.5 Hz), 3.02(2H, t, J=7.5 Hz), 3.10–3.30 (4H, m), 3.82 (3H, s), 4.13 (2H, t, J=8.4Hz), 4.40–4.50 (2H, m), 6.80–6.95 (2H, m), 7.10–7.30 (2H, m), 7.67 (1H,s), 7.71 (1H, s).

Reference Example 186 tert-Butyl6-oxo-6-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)hexyl(2-phenylethyl)carbamate

Using 6-(6-bromohexanoyl)-2H-1,4-benzoxazin-3(4H)-one (1.00 g) obtainedin Reference Example 8 and 2-phenylethylamine (800 mg) according to thesame method as that of Reference Example 19, the title compound (842 mg)was obtained as a pale yellow oil.

¹H NMR (300 MHz, CDCl₃) δ 1.20–1.85 (6H, m), 1.47 (9H, s), 2.75–2.95(4H, m), 3.00–3.25 (2H, m), 3.30–3.45 (2H, m), 4.68 (2H, s), 7.00 (1H,d, J=8.7 Hz), 7.10–7.35 (5H, m), 7.50–7.65 (2H, m), 8.90–9.25 (1H, br).

Reference Example 187 tert-Butyl2-(2-methoxyphenyl)ethyl[6-oxo-6-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)hexyl]carbamate

Using 6-(6-bromohexanoyl)-2H-1,4-benzoxazin-3(4H)-one (1.00 g) obtainedin Reference Example 8 and 2-(2-methoxyphenylethylamine (925 mg)according to the same method as that of Reference Example 19, the titlecompound (974 mg) was obtained as a pale yellow oil.

¹H NMR (200 MHz, CDCl₃) δ 1.20–1.85 (6H, m), 1.46 (9H, s), 2.75–2.95(4H, m), 3.00–3.25 (2H, m), 3.30–3.45 (2H, m), 3.82 (3H, s), 4.68 (2H,s), 6.80–7.25 (5H, m), 7.50–7.65 (2H, m), 8.90–9.30 (1H, br).

Reference Example 188 tert-Butyl2-(2-chlorophenyl)ethyl[6-oxo-6-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)hexyl]carbamate

Using 6-(6-bromohexanoyl)-2H-1,4-benzoxazin-3(4H)-one (1.00 g) obtainedin Reference Example 8 and 2-(2-chlorophenyl)ethylamine (952 mg)according to the same method as that of Reference Example 19, the titlecompound (974 mg) was obtained as a pale yellow oil.

¹H NMR (200 MHz, CDCl₃) δ 1.20–1.85 (6H, m), 1.44 (9H, s), 2.80–3.25(6H, m), 3.35–4.45 (2H, m), 4.69 (2H, s), 6.95–7.40 (5H, m), 7.50–7.65(2H, m), 9.00–9.40 (1H, br).

Reference Example 189N-{5-[3-(1-acetyl-4-piperidinyl)propanoyl]-2-methoxyphenyl}-2,2,2-trifluoroacetamide

3-(1-Acetyl-4-piperidinyl)propionic acid (10.0 g) was added by portionsto thionyl chloride (30 ml) at room temperature. After stirring at roomtemperature for 30 minutes, thionyl chloride was evaporated underreduced pressure to give the crude product of3-(1-acetyl-4-piperidinyl)propionyl chloride Aluminum chloride (20 g)was added by portions to a suspension of the crude product, and2,2,2-trifluoro-N-(2-methoxyphenyl)acetamide (10.0 g) at roomtemperature After stirring at room temperature for 1 hour, the reactionmixture was poured into ice (200 g), extracted with ethyl acetate, andwashed with brine. The organic layer was dried over anhydrous magnesiumsulfate, the solvent was evaporated under reduced pressure, theresulting residue was purified by silica gel chromatography (elutingsolvent; ethyl acetate), and the solvent was evaporated to give thetitle compound as colorless crystals (8.83 g) having a melting point of77 to 79° C.

¹H NMR (200 MHz, CDCl₃) δ 1.00–1.30 (3H, m), 1.50–1.90 (4H, m), 2.09(3H, s), 2.53 (1H, tt, J=12.8, 2.8 Hz), 2.90–3.05 (3H, m), 3.70–3.90(1H, m), 4.02 (3H, s), 4.50–4.70 (1H, m), 7.02 (1H, d, J=8.8 Hz), 7.89(1H, dd, J=8.8, 2.2 Hz), 8.50–8.65 (1H, br), 8.95 (1H, d, J=2.2 Hz).

Reference Example 1903-(1-Acetyl-4-piperidinyl)-1-(3-amino-4-methoxyphenyl)-1-propanone

A suspension ofN-{5-[3-(1-acetyl-4-piperidinyl)propanoyl]-2-methoxyphenyl}-2,2,2-triofluoroacetamide(3.00 g) obtained in Reference Example 189 in saturated potassiumcarbonate aqueous solution (20 ml), water (10 ml) and methanol (30 ml)was stirred at room temperature for 5 hours. Methanol was evaporatedunder reduced pressure, the residue was extracted with ethyl acetate,and washed with brine. The organic layer was dried over anhydrousmagnesium sulfate and the solvent was evaporated under reduced pressureto give the title compound as colorless crystals (1.57 g) having amelting point of 101 to 103° C.

¹H NMR (200 MHz, CDCl₃) δ 1.00–1.25 (3H, m), 1.45–1.85 (4H, m), 2.08(3H, s), 2.52 (1H, tt, J=12.8, 3.0 Hz), 2.85–3.10 (3H, m), 3.70–3.90(1H, m), 3.91 (3H, s), 3.90–4.00 (2H, br), 4.50–4.70 (1H, m), 6.80 (1H,d, J=8.4 Hz), 7.30–7.45 (2H, m). elementary analysis as C₁₇H₂₄N₂O₃calculation value: C, 67.08; H, 7.95; N, 9.20. experimental value: C,66.83; H, 7.73; N, 9.18.

Reference Example 1911-(3-Amino-4-methoxyphenyl)-3-(4-piperidinyl)-1-propanonedihydrochloride

A solution of3-(1-acetyl-4-piperidinyl)-1-(3-amino-4-methoxyphenyl)-1-propanone (500mg) obtained in Reference Example 190 in concentrated hydrochloric acid(10 ml) was stirred at 130° C. for 6 hours. The solvent was evaporated,the residue was filtered, and washed successively with ethanol anddiethyl ether. The resulting crystals, were air-dried to give the titlecompound as colorless crystals (544 mg) having a melting point of 210°C. (dec).

¹H NMR (300 MHz, DMSO-d₆) δ 1.25–1.45 (2H, m), 1.50–1.65 (3H, m),1.75–1.90 (2H, m), 2.70–2.90 (2H, m), 2.97 (2H, t, J=6.9 Hz), 3.15–3.25(2H, m), 3.94 (3H, s), 7.00–9.50 2H, br), 7.20 (1H, d, J=8.4 Hz),7.80–7.90 (2H, m), 8.75–9.25 (3H, br).

Reference Example 1928-(3-Chloropropanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one

Using 1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (10.0 g) and3-chloropropanoyl chloride (6.06 ml) according to the same method asthat of Reference Example 1, the title compound (12.0 g) was obtained ascolorless crystals having a melting point of 154 to 155° C.

¹H NMR (300 MHz, CDCl₃) δ 2.72 (2H, t, J=7.8 Hz), 3.03 (2H, t, J=7.8Hz), 3.23 (2H, t, J=8.7 Hz), 3.39 (2H, t, J=6.9 Hz), 3.91 (2H, t, J=6.9Hz), 4.13 (2H, t, J=8.7 Hz), 7.67 (1H, s), 7.71 (1H, s).

Reference Example 193 tert-Butyl(±)-2,3-dihydro-1H-inden-1-yl-[5-oxo-5-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)pentyl]carbamate

Using8-(5-chloropentanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(500 mg) obtained in Reference Example 1 and(±)-2,3-dihydro-1H-inden-1-ylamine, (683 mg) according to the samemethod as that of Reference Example 19, the title compound (332 mg) wasobtained as a pale yellow oil.

¹H NMR (200 MHz, CDCl₃) δ 1.20–2.10 (13H, m), 2.60–3.10 (12H, m),3.10–3.30 (2H, m), 3.50–3.65 (1H, m), 4.00–4.20 (2H, m), 7.10–7.30 (3H,m), 7.60–7.80 (3H, m).

Reference Example 194 tert-Butyl2,3-dihydro-1H-inden-2-yl-[5-oxo-5-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)pentyl]carbamate

Using8-(5-chloropentanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(500 mg) obtained in Reference Example 1 and2,3-dihydro-1H-inden-2-ylamine (683 mg) according to the same method asthat of Reference Example 19, the title compound(461 mg) was obtained asa pale yellow oil.

¹H NMR (200 MHz, CDCl₃) δ 1.42 (9H, s), 1.50–1.75 (2H, m), 1.80–2.00(2H, m), 2.72 (2H, t, J=7.6 Hz), 2.80–3.30 (11H, m), 3.50–3.65 (1H, m),4.00–4.20 (3H, m), 7.05–7.20 (4H, m), 7.60–7.75 (2H, m).

Reference Example 1956-(5-Chloropentanoyl)-3,4-dihydroquinolin-2(1H)-one

Using 3,4-dihydroquinolin-2(1H)-one (2.94 g) and 5-chloropentanoylchloride (3.7 g) according to the same method as that of ReferenceExample 1, the title compound was obtained as colorless crystals (1.59g) having a melting point of 145 to 146° C.

¹H NMR (400 MHz, CDCl₃) δ 1.84–1.94 (4H, m), 2.67 (2H, t, J=6.4 Hz),2.96 (2H, t, J=6.8 Hz), 3.05 (2H, t, J=7.5 Hz), 3.59 (2H, t, J=6.4 Hz),6.90 (1H, d, J=8.7 Hz), 7.81 (1H, d, J=8.7 Hz), 7.82 (1H, s), 9.28 (1H,s). IR (KBr) νcm⁻¹: 3273, 1680, 1604, 1361, 1314, 1227, 1145.

Reference Example 196 tert-Butyl5-oxo-5-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pentyl(2-phenylethyl)carbamate

Using 6-(5-chloropentanoyl)-3,4-dihydroquinolin-2(1H)-one (399 mg)obtained in Reference Example 195 and 2-phenylethylamine (454 mg)according to the same method as that of Reference Example 19, the tilecompound (530 mg), was obtained as a pale yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 1.44 (9H, s), 1.51–1.73 (4H, m), 2.68 (2H, t,J=7 Hz), 2.75–2.86 (2H, m), 2.88–2.98 (2H, m), 3.03 (2H, t, J=7 Hz),3.08–3.24 (2H, m), 3.32–3.42 (2H, m), 6.87 (1H, d, J=8.4 Hz), 7.18–7.30(5H, m), 7.79 (1H, d, J=6 Hz), 7.80 (1H, s), 9.09 (1H, br).

Reference Example 197 tert-Butyl2-(2-methoxyphenyl)ethyl[5-oxo-5-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pentyl]carbamate

Using 6-(5-chloropentanoyl)-3,4-dihydroquinolin-2(1H)-one (399 mg)obtained in Reference Example 195 and 2-(2-methoxyphenyl)ethylamine (567mg) according to the same method as that of Reference Example 19, thetitle compound (638 mg) was obtained as a pale yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 1.43 (9H, s), 1.51–1.72 (4H, m), 2.68 (2H, t,J=8 Hz), 2.78–2.88 (2H, m), 2.89–2.97 (2H, m), 3.03 (2H, t, J=7.3 Hz),3.08–3.28 (2H, m), 3.30–3.42 (2H, m), 3.82 (3H, s) 6.83 (1H, d, J=8.4Hz), 6.87–6.90 (2H, m), 7.09–7.21 (2H, m), 7.79 (1H, d, J=6 Hz), 7.80(1H, s) 9.31 (1H, br).

Reference Example 198 tert-Butyl2-(2-chlorophenyl)ethyl[5-oxo-5-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pentyl]carbamate

Using 6-(5-chloropentanoyl)-3,4-dihydroquinolin-2(1H)-one (399 mg)obtained in Reference Example 195 and 2-(2-chlorophenyl)ethylamine (584mg) according to the same method as that of Reference Example 19, thetitle compound (682mg) was obtained as a pale yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 1.41 (9H, s), 1.51–1.73 (4H, m), 2.68 (2H, t,J=7.3 Hz), 2.91–3.01 (4H, m), 3.03 (2H, t, J=7.3 Hz), 3.12–3.25 (2H, m),3.41 (2H, t, J=7.3 Hz), 6.87 (1H, d, J=8.4 Hz), 7.17–7.20 (3H, m), 7.33(1H, d, J=7 Hz), 7.80 (1H, d, J=6 Hz), 7.81 (1H, s) 9.01 (1H, br).

Reference Example 199 6-(6-Bromohexanoyl)-3,4-dihydroquinolin-2(1H)-one

Using 3,4-dihydroquinolin-2(1H)-one (2.94 g) and 6-bromohexanoylchloride (5.1 g) according to the same method as that of ReferenceExample 1, the title compound was obtained as colorless crystals (1.62g) having a melting point of 116 to 117° C.

¹H NMR (400 MHz, CDCl₃) δ 1.50–1.57 (2H, m), 1.73–1.79 (2H, m),1.88–1.96 (2H, m), 2.69 (2H, t, J=6.4 Hz), 2.95 (2H, t, J=7.5 Hz), 3.05(2H, t, J=7.5 Hz), 3.43 (2H, t, J=6.4 Hz), 6.92 (1H, d, J=8.7 Hz), 7.80(1H, d, J=8.7 Hz), 7.85 (1H, s), 9.51 (1H, s). IR (KBr) νcm⁻¹: 3192,3055, 1679, 1593, 1367, 1321, 1254.

Reference Example 200 tert-Butyl2-(2-methoxyphenyl)ethyl[5-(1-methyl-2-oxo-1,2,3,4-tertahydroquinolin-6-yl)-5-oxopentyl]carbamate

Using 6-(5-chloropentanoyl)-1-methyl-3,4-dihydroquinolin-2(1H)-one (224mg) obtained in Reference Example 154 and 2-(2-methoxyphenyl)ethylamine(266 mg) according to the same method as that of Reference Example 19,the title compound (230 mg) was obtained as a pale yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 1.43 (9H, s), 1.51–1.76 (4H, m), 2.68 (2H, t,J=7 Hz), 2.77–2.88 (2H, m), 2.96 (4H, t, J=7 Hz), 3.12–3.24 (2H, m),3.32–3.37 (2H, m), 3.38 (3H, s), 3.82 (3H, s), 6.83–6.89 (2H, m), 7.01(1H, d, J=8.5 Hz), 7.06–7.21 (2H, m), 7.78 (1H, s) 7.87 (1H, d, J=8 Hz).

Reference Example 201 tert-Butyl2-(2-chlorophenyl)ethyl[5-(1-methyl-2-oxo-1,2,3,4-tertahydro-6-quinolinyl)-5-oxopentyl]carbamate

Using 6-(5-chloropentanoyl)-1-methyl-3,4-dihydroquinolin-2(1H)-one (224mg) obtained in Reference Example 154 and 2-(2-chlorophenyl)ethylamine(274 mg) according to the same method as that of Reference Example 19,the title compound (244 mg) was obtained as a pale yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 1.41 (9H, s), 1.51–1.76 (4H, m), 2.68 (2H, t,J=7 Hz), 2.92–2.98 (6H, m), 3.12–3.24 (2H, m), 3.39 (3H, s), 3.41 (2H,t, J=7 Hz), 7.02 (1H, d, J=8.5 Hz), 7.14–7.28 (3H, m), 7.33 (1H, d, J=7Hz), 7.78 (1H, s,), 7.87 (1H, d, J=8 Hz).

Reference Example 202(±)-5-[[2-(2-Chlorophenyl)ethyl](methyl)amino]hexanoic acid

4.75 g (30 mmol) of Ethyl 5-oxohexanoate was placed into a 300 mlfour-neck flask, and 100 ml of THF was added thereto to dissolve them.At room temperature, 5.1 g (30 mmol) ofN-methyl-2-(2-chlorophenyl)ethylamine was added, and further 8.3g (39mmol) of NaBH(OAc)₃ was added. After stirring overnight at roomtemperature, the reaction mixture was concentrated, and each 50 ml of 6%sodium bicarbonate was added to the residue to neutralize. The liberatedoil was extracted with ethyl acetate (50 ml×2), dried over MgSO₄, andconcentrated to give 5-ethyl(±)-[[2-(2-chlorophenyl)ethyl](methyl)amino]hexanoate as a pale yellowoil (6.38 g).

¹H NMR (400 MHz, CDCl₃) δ 0.94 (3H, d, J=6.6 Hz), 1.19–1.28 (1H, m),1.25 (3H, t, J=7.0 Hz), 1.44–1.52 (1H, m), 1.56–1.64 (2H, m), 2.25 (2H,t, J=7.3 Hz), 2.29 (3H, s), 2.51–2.69 (3H, m), 2.84–2.89 (2H, m), 4.12(2H, q, J=7.0 Hz), 7.12–7.25 (3H, m), 7.32 (1H, dd, J=7.6, 1.5 Hz). IR(neat) νcm⁻¹: 1735, 1.652, 1476, 1249, 1177, 1053, 752.

6.2 g (20 mmol) of 5-ethyl(±)-[[2-(2-chlorophenyl)ethyl](methyl)amino]hexanoate was placed into a100 ml eggplant-type flask, and EtOH (10 ml) was added to dissolve themAt room temperature, 1.35 g (24 mmol) of KOH dissolved in 10 ml of waterwas added. After stirring at room temperature for 16 hours, EtOH wasevaporated, 4 ml (24 mmol) of 6N hydrochloric acid was added to theresidue to neutralize, concentrated to dryness, and 20 ml of EtOH wasadded to, the residue to dissolve it. The insolubles were filtered off,and the filtrated was concentrated to dryness to give the title compoundas a pale yellow oil (6.16 g).

¹H NMR (400 MHz, CDCl₃) δ 1.21 (3H, d, J=6.6 Hz), 1.41–1.51 (1H, m),1.65–1.74 (2H, m), 1.99–2.01 (1H, m), 2.24–2.41 (2H, m), 2.61(3H, s),2.92–3.04 (3H, m), 3.20 (2H, t, J=8.3 Hz), 7.16–7.23 (2H, m), 7.32–7.36(2H, m), 9.35 (1H, br). IR (neat) νcm⁻¹: 3418, 1718, 1630, 1476, 1398,1053, 757.

Reference Example 2035-(5-Chloropentanoyl)-N-methyl-2,3-dihydro-1-benzofuran-7-sulfonamide

Using 5-(5-chloropentanoyl)-2,3-dihydro-1-benzofuran-7-sulfonyl chloride(5.06 g) obtained in Reference Example 69 and a 40% methylamine-methanolsolution (2.6 g) according to the same method as that of ReferenceExample 66, the title compound was obtained as colorless crystals (4.82g) having a melting point of 120 to 121° C.

¹H NMR (400 MHz, CDCl₃) δ 1.85–1.92 (4H, m), 2.66 (3H, d, J=5.4 Hz),2.98–3.01 (2H, m), 3.35 (2H, t, J=8.8 Hz), 3.57–3.60 (2H, m), 4.78 (1H,q, J=5.4 Hz), 4.88 (2H, t, J=8.8 Hz), 8.06 (1H, s), 8.22 (1H, s). IR(KBr) νcm⁻¹: 3326, 1664, 1603, 1586, 1480, 1383, 1357, 1328, 1266, 1161,1115, 868, 579.

Reference Example 2045-(5-Chloropentanoyl)-N,N-dimethyl-2,3-dihydro-1-benzofuran-7-sulfonamide

Using 5-(5-chloropentanoyl)-2,3-duhydro-1-benzofuran-7-sulfonyl chloride(5.06 g) obtained in Reference Example 69 and dimethylamine (3 ml)according to the same method as that of Reference Example 66, the titlecompound was obtained as colorless crystals (4.93 g) having a meltingpoint of 113 to 114° C.

¹H NMR (400 MHz, CDCl₃) δ 1.84–1.93(4H, m), 2.84 (6H, s), 2.96–3.00 (2H,m), 3.33 (2H, t, J=8.8 Hz), 3.57–3.60 (2H, m), 4.83 (2H, q, J=5.4 Hz),8.03 (1H, s), 8.18 (1H, s). IR (KBr) νcm⁻¹: 1681, 1603, 1479, 1462,1422, 1340, 1264, 1154, 1119, 956, 710, 583.

Reference Example 2055-Chloro-1-(2,3-dihydro-2,2-dimethyl-1-benzofuran-5-yl)pentane-1-one

Using 2,2-dimethyl-2,3-dihydro-1-benzofuran (3.0 g) and 5-chlorovalerylchloride (3.4 g) according to the same method as that of ReferenceExample 1, the title compound was obtained as a fine yellow oil (3.6 g).

¹H NMR (400 MHz, CDCl₃) δ 1.50 (6H, s), 1.83–1.92 (4H, m), 2.91–2.95(2H, m), 3.04 (2H, s), 3.56–3.59 (2H, m), 6.74 (1H, d, J=8.8 Hz), 7.79(1H, d, J=8.8 Hz), 7.81 (1H, s). IR (neat) νcm⁻¹: 1674, 1607, 1490,1441, 1372, 1245, 1225, 1094, 868

Reference Example 2065-Chloro-1-(3,4-dihydro-2H-chromen-6-yl)pentane-1-one

Using chroman (5.40 g) and 5-chlorovaleryl chloride (6.82 g) accordingto the same method as that of Reference Example 1, the title compoundwas obtained as a fine yellow oil (7.9, g).

¹H NMR (400 MHz, CDCl₃) δ 1.83–1.91 (4H, m), 2.00–2.06 (2H, m), 2.83(2H, t, J=6.6 Hz), 2.91–2.96 (2H, m,) 3.58 (2H, t, J=6.6 Hz), 4.24 (2H,t, J=5.2 Hz), 6.81 (1H, d, J=8.8 Hz), 7.70 (1H, s), 7.71 (1H, d, J=8.8Hz). IR (neat) νcm⁻¹: 1675, 1606, 1577, 1499, 1317, 1247, 1162, 1133,1118, 1060, 1005, 821.

Reference Example 207 6-(5-Chloropentanoyl)chroman-8-sulfonyl chloride

Using 5-chloro-1-(3,4-dihydro-2H-chromen-6-yl)pentan-1-one (5.1 g)obtained in Reference Example 206 according to the same method as thatof Reference Example 65, the title compound was obtained as a colorlessoil (3.57 g).

¹H NMR (400 MHz, CDC₃) δ 1.85–1.94 (4H, m), 2.14–2.19 (2H, m), 2.93–3.00(4H, m), 3.59 (2H, t, J=5.9 Hz), 4.54 (2H, t, J=5.6 Hz), 8.03 (1H, s),8.33 (1H, s). IR (neat) νcm⁻¹: 1686, 1600, 1567, 1485, 1371, 1278, 1258,1172, 1132, 1002, 579, 557.

Reference Example 208 6-(5-Chloropentanoyl)-8-chromansulfonamide

Using 6-(5-chloropentanoyl)-8-chromansulfonyl chloride (3.5 g) obtainedin Reference Example 207 according to the same method as that ofReference Example 66, the title compound was obtained as colorlesscrystals (2.9 g) having a melting point of 168 to 169° C.

¹H NMR (400 MHz, CDCl₃) δ 1.67–1.80 (4H, m), 1.97 (2H, t, J=5.3 Hz),2.86 (2H, t, J=6.1 Hz), 3.00 (2H, t, J=6.6 Hz), 3.67 (2H, t, J=6.1 Hz),4.36 (2H, t, J=5.3 Hz), 7.15 (2H, s), 7.94 (1H, d, J=1.8 Hz), 8.10 (1H,d, J=1.8 Hz). IR (KBr) νcm⁻¹: 3376, 3272, 1695, 1599, 1482, 1459, 1419,1309, 1244, 1137, 906, 744.

Reference Example 209 tert-Butyl5-(2,3-dihydro-2,2-dimethyl-1-benzofuran-5-yl)-5-oxopentyl[2-(2-chlorophenyl)ethyl]carbamate

Using5-chloro-1-(2,3-dyhydro-2,2-dimethyl-1-benzofuran-5-yl)pentan-1-one (543mg) obtained in Reference Example 205 and 2-(2-chlorophenyl)ethylamine(778 mg) according to the same method as that of Reference Example 19,the title compound was obtained as a fine yellow oil (612 mg).

¹H NMR (400 MHz, CDCl₃) δ 1.41 (9H, s), 1.49 (6H, s), 1.51–1.72 (4H, m),2.85–3.00 (4H, m), 3.03 (2H, s), 3.07–3.25 (2H, m), 3.41 (2H, t, J=7.3Hz), 6.73 (1H, d, J=9.1 Hz), 7.12–7.34 (4H, m), 7.80 (2H, br.s).

Reference Example 210 tert-Butyl5-(3,4-dihydro-2H-chromen-6-yl)-5-oxopentyl[2-(2-chlorophenyl)ethyl]carbamate

Using 5-chloro-1-(3,4-dihydro-2H-chromen-6-yl)pentan-1-one (505 mg)obtained in Reference Example 206 and 2-(2-chlorophenyl)ethylamine (778mg) according to the same method as that of Reference Example 19, thetitle compound was obtained as a fine yellow oil (793 mg).

¹H NMR (400 MHz, CDCl₃) δ 1.41 (9H, s), 1.51–1.73 (4H, m), 2.01 (2H, t,J=6 Hz), 2.82 (2H, t, J=6 Hz), 2.85–3.01 (4H, m), 3.07–3.23 (2H, m),3.41 (2H, t, J=7 Hz), 4.23 (2H, q, J=5.3 Hz), 6.80 (1H, d, J=9.1 Hz),7.12–7.34 (4H, m), 7.70 (2H, br.s).

Reference Example 211 tert-Butyl5-{7-[(methylamino)sulfonyl]-2,3-dihydro-1-benzofuran-5-yl}-5-oxopentyl[2-(2-methoxyphenyl)ethyl]carbamate

Using5-(5-chloropentanoyl)-N-methyl-2,3-dihydro-1-benzofuran-7-sulfonamide(664 mg) obtained in Reference Example 203 and2-(2-methoxyphenyl)ethylamine (762 mg) according to the same method asthat of Reference Example 19, the title compound was obtained as acolorless oil (864 mg).

¹H NMR (400 MHz, CDCl₃) δ 1.43 (9H, s), 1.50–1.73 (4H, m), 2.65 (3H, d,J=5.4 Hz), 2.82 (2H, br.s), 2.95 (2H, br.s), 3.08–3.23 (2H, m),3.31–3.37 (4H, m), 3.83 (3H, s), 4.81(1H, q, J=5.4 Hz), 4.86 (2H, t,J=8.8 Hz), 6.83–6.89 (2H, m), 7.09–7.21 (2H, m), 8.04 (1H, d, J=1.5 Hz),8.22 (1H, d, J=1.5 Hz).

Reference Example 212 tert-Butyl5-{7-[(methylamino)sulfonyl]-2,3-dihydro-1-benzofuran-5-yl}-5-oxopentyl[2-(2-chloroyphenyl)ethyl]carbamate

Using5-(5-chloropentanoyl)-N-methyl-2,3-dihydro-1-benzofuran-7-sulfonamide(664 mg) obtained in Reference Example 203 and2-(2-chlorophenyl)ethylamine (778 mg) according to the same method asthat of Reference Example 19, the title compound was obtained ascolorless crystals (890 mg) having a melting point of 87 to 88° C.

¹H NMR (400 MHz, CDCl₃) δ 1.41 (9H, s), 1.50–1.73 (4H, m), 2.66 (3H, d,J=5.4 Hz), 2.95 (4H, br.s), 3.08–3.27 (2H, m), 3.34 (2H, t, J=8.8 Hz),3.41 (2H, t, J=7.5 Hz), 4.78 (1H, q, J=5.4 Hz), 4.87 (2H, t, J=8.8 Hz),7.13–7.29 (3H, m), 7.33 (1H, d, J=6.6 Hz), 8.04 (1H, d, J=1.2 Hz), 8.22(1H, d, J=1.2 Hz).

Reference Example 213 tert-Butyl5-{7-[(dimethylamino)sulfonyl]-2,3-dihydro-1-benzofuran-5-yl}-5-oxopentyl[2-(2-methoxyphenyl)ethyl]carbamate

Using5-(5-chloropentanoyl)-N,N-dimethyl-2,3-dihydro-1-benzofuran-7-sulfonamide(692 mg) obtained in Reference Example 204 and2-(2-methoxyphenyl)ethylamine (762 mg) according to the same method asthat of Reference Example 19, the title compound was obtained as acolorless oil (875 mg).

¹H NMR (400 MHz, CDCl₃) δ 1.43 (9H, s), 1.50–1.73 (4H, m), 2.79–2.87(2H, m), 2.83(6H, s), 2.94 (2H, br.s), 3.08–3.23 (2H, m), 3.29–3.51 (4H,m), 3.83 (3H, s), 4.82 (2H, t, J=8.8 Hz), 6.83–6.88 (2H, m), 7.09–7.21(2H, m), 8.01 (1H, d, J=1.5 Hz), 8.17 (1H, d, J=1.5 Hz).

Reference Example 214 tert-Butyl2-(2-chlorophenyl)ethyl(5-{7-[(dimethylamino)sulfonyl]-2,3-dihydro-1-benzofuran-5-yl}-5-oxopentyl)carbamate

Using5-(5-chloropentanoyl)-N,N-dimethyl-2,3-dihydro-1-benzofuran-7-sulfonamide(692 mg) obtained in Reference Example 204 and2-(2-chlorophenyl)ethylamine (778 mg) according to the same method asthat of Reference Example 19, the title compound was obtained ascolorless crystals (960 mg) having a melting point of 86 to 87° C.

¹H NMR (400 MHz, CDCl₃) δ 1.41 (9H, s), 1.50–1.73 (4H, m), 2.84 (6H, s),2.95 (4H, br.s), 3.08–3.25 (2H, m), 3.32 (2H, t, J=8.8 Hz), 3.41 (2H, t,J=7.5 Hz), 4.82 (2H, t, J=8.8 Hz), 7.13–7.29 (3H, m), 7.33 (1H, d, J=6.6Hz), 8.01 (1H, d, J=1.4 Hz), 8.17 (1H, d, J=1.4 Hz).

Reference Example 215 tert-Butyl5-[8-(aminosulfonyl)-3,4-dihydro-2H-chromen-6-yl]-5-oxopentyl[2-(2-methoxyphenyl)ethyl]carbamate

Using 6-(5-chloropentanoyl)-8-chromansulfonamide (664 mg) obtained inReference Example 208 and 2-(2-methoxyphenyl)ethylamine (762 mg)according to the same method as that of Reference Example 19, the titlecompound was obtained as a colorless oil (650 mg).

¹H NMR (400 MHz, CDCl₃) δ 1.40 (9H, s), 1.51–1.70 (4H, m), 2.11 (2H,br.s), 2.79–2.89 (6H, m), 3.07–3.23 (2H, m), 3.33 (2H, t, J=7.1 Hz),3.82 (3H, s), 4.47 (2H, t, J=5.1 Hz), 5.29 (2H, s), 6.83–6.88 (2H, m),7.06–7.20 (2H, m), 7.89 (1H, s), 8.27 (1H, s).

Reference Example 216 tert-Butyl5-[8-(aminosulfonyl)-3,4-dihydro-2H-chromen-6-yl]-5-oxopentyl[2-(2-chlorophenyl)ethyl]carbamate

Using 6-(5-chloropentanoyl)-8-chromansulfonamide (664 mg) obtained inReference Example 208 and 2-(2-chlorophenyl)ethylamine (778 mg)according to the same method as that of Reference Example 19, the titlecompound was obtained as a colorless oil (677 mg).

¹H NMR (400 MHz, CDCl₃) δ 1.38 (9H, s), 1.51–1.71 (4H, m), 2.12 (2H,br.s), 2.89–2.93 (6H, m), 3.11–3.21 (2H, m), 3.39 (2H, br.s), 4.47 (2H,t, J=5.1 Hz), 5.23 (2H, s), 7.13–7.34 (4H, m), 7.90 (1H, s), 8.27 (1H,s).

Reference Example 2175-(5-Chloropentanoyl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one and6-(5-chloropentanoyl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one

Using 1-methyl-1,3-dihydro-2H-benzimidazol-2-one (4.45 g) and5-chlorovaleryl chloride (5.58 g) according to the same method as thatof Reference Example 1, a mixture of the title compound (1.5:1) wasobtained as colorless crystals (5.5 g).

¹H NMR (400 MHz, DMSO-d₆) δ 1.67–1.81 (4H, m), 2.99–3.05 (2H, m), 3.30(3H×3/5, s), 3.32 (3H×2/5, s), 3.61–3.69 (2H, m,), 7.03 (1H×2/5, d,J=8.3 Hz), 7.14 (1H×3/5, d, J=8.3 Hz), 7.49 (1H×3/5, d, J=1.5 Hz), 7.64(1H×2/5, d, J.=1.5 Hz), 7.69 (1H×2/5, dd, J=8.3, 1.5 Hz), 7.73 (1H×3/5,dd, J=8.8, 1.5 Hz), 11.09 (1H×3/5, s), 11.23 (1H×2/5, s).

Reference Example 218 tert-Butyl2-(2-chlorophenyl)ethyl[5-(1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-5-oxopentyl]carbamate(A) and tert-butyl2-(2-chlorophenyl)ethyl[5-(3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-5-oxopentyl]carbamate(B)

Using a mixture of5-(5-chloropentanoyl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one and6-(5-chloropentanoyl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (1.60g) obtained in Reference Example 217 and 2-(2-chlorophenyl)ethylamine(2.33 g) according to the same method as that of Reference Example 19,the title compound was obtained as colorless crystals (1-methyl compound(A): 1.0 g) having a melting point of 121 to 122° C. and a fine yellowoil (3-methyl compound (B): 645 mg). p ¹H NMR (1-methyl compound (A);400 MHz, CDCl₃) δ 1.41 (9H, s), 1.52–1.76 (4H, m), 2.97 (4H, br.s),3.14–3.25 (2H, m), 3.42 (2H, t, J=7.0 Hz), 3.45 (3H, s), 6.98 (1H, d,J=7.8 Hz), 7.16–7.33 (4H, m), 7.75 (1H, s), 7.77 (1H, d, J=7.8 Hz),10.76–10.84 (1H, m).

¹H NMR (3-methyl compound (B); 400 MHz, CDCl₃) δ 1.41 (9H, s), 1.52–1.76(4H, m), 2.95–3.01 (4H, m), 3.15–3.25 (2H, m), 3.42 (2H, t, J=7.3 Hz),3.48 (3H, s), 7.15 (1H, d, J=8.0 Hz), 7.16–7.34 (4H, m), 7.65 (1H, s),7.76 (1H, d, J=8.0 Hz), 10.65 (1H, br.s).

Reference Example 219 tert-Butyl2-(2-chloro-4-hydroxyphenyl)ethyl[5-(1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-5-oxopentyl]carbamate(A) and tert-butyl2-(2-chloro-4-hydroxyphenyl)ethyl[5-(3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-5-oxopentyl]carbamate(B)

Using a mixture of5-(5-chloropentanoyl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one and6-(5-chloropentanoyl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (1.60g) obtained in Reference Example 217 and 4-(2-aminoethyl)-3-chlorophenolhydrobromide (3.3 g) according to the same method as that of ReferenceExample 82, the title compound was obtained as a fine yellow oil(1-methyl compound (A): 428 mg) and colorless crystals (3-methylcompound (B): 290 mg) having a melting point of 157 to 158° C.

¹H NMR (1-methyl compound (A); 400 MHz, CDCl₃) δ 1.41 (9H, s), 1.51 (2H,br.s), 1.62–1.72 (2H, m), 2.84–2.91 (4H, m), 3.03–3.12 (2H, m), 3.36(2H, t, J=7.1 Hz), 3.45 (3H, s), 6.72 (1H, d, J=8.3 Hz), 6.92 (1H,br.s), 6.97 (1H, d, J=7.6 Hz), 7.01 (1H, d, J=8.3 Hz), 7.67 (1H, br.s),7.72 (1H, br.s), 7.77 (1H, d, J=7.6 Hz), 10.08–10.23 (1H, m).

¹H NMR (3-methyl compound (B); 400 MHz, CDCl₃) δ 1.29 (9H, s), 1.45–1.58(4H, m), 2.74 (2H, t, J=7.3 Hz), 3.00 (2H, t, J=6.6 Hz), 3.05–3.17 (2H,m), 3.27 (2H, br.s), 3.32 (3H, s), 6.65 (1H, dd, J=8.3, 2.4 Hz), 6.77(1H, d, J=2.4 Hz), 7.04 (2H, br.d, J=8.0 Hz), 7.64 (1H, br.s), 7.69 (1H,d, J=8.0 Hz), 9.66 (1H, s), 11.22 (1H, s).

Reference Example 220 tert-Butyl2-(2-chloro-4-hydroxyphenyl)ethyl[5-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-5-oxopentyl]carbamate

Using5-(5-chloropentanoyl)-1,3-dimethyl-1,3-dihydro-2H-benzimidazol-2-one(562 mg) obtained in Reference Example 10 and4-(2-aminoethyl)-3-chlorophenol hydrobromide (1.1 g) according to thesame method as that of Reference Example 82, the title compound wasobtained as a fine yellow oil (272 mg).

¹H NMR (400 MHz, CDCl₃) δ 1.40 (9H, s), 1.60 (2H, br.s), 1.68–1.74 (2H,m), 2.85 (2H, m), 3.00 (2H, t, J=7.3 Hz), 3.18 (2H, t, J=7.3 Hz), 3.36(2H, br.s), 3.46 (6H, s), 6.70 (1H, d, J=8.0 Hz), 6.90 (1H,br.s),6.95–7.24 (3H, m), 7.62 (1H, d, J=1.7 Hz), 7.78 (1H, dd, J=8.0, 1.7 Hz).

Reference Example 2211-Methyl-5,6-dihydro-1H,4H-[1,2,5]thiadiazolo[4,3,2-ij]quinoline2,2-dioxide

Using 5,6-dihydro-1H,4H-[1,2,5]thiadiazolo[4,3,2-ij]quinoline 2,2-oxideaccording to the same method as that of Reference Example 132, the titlecompound was obtained as brown crystals having a melting point of 103 to104° C.

¹H NMR (200 MHz, CDCl₃) δ 2.17 (2H, quintet, J=6.2 Hz), 2.77 (2H, t,J=6.4 Hz), 3.25 (3H, s), 3.69 (2H, t, J=5.6 Hz), 6.56 (1H, d, J=7.8 Hz),6.74 (1H, d, J=6.8 Hz), 6.88 (1H, t, J=7.6 Hz).

Reference Example 2225-Chloro-1-(1-methyl-2,2-dioxide-5,6-dihydro-1H,4H-[1,2,5]thiadiazolo[4,3,2-ij]quinolin-8-yl)-1-pentanone

Using 1-methyl-5,6-dihydro-1H,4H-[1,2,5]thiadiazolo[4,3,2-ij]quinoline2,2-dioxide and 5-chlorovaleryl chloride according to the same method asthat of Reference Example 1, the title compound was obtained as pale redcrystals having a melting point of 99 to 100° C.

¹H NMR (200 MHz, CDCl₃) δ 1.89 (4H, t, J=2.8 Hz), 2.21 (2H, quintet,J=5.6 Hz), 2.83 (2H, t, J=6.2 Hz), 2.96 (2H, t, J=1 6.8 Hz), 3.21 (3H,s), 3.58 (2H, t, J=6.8 Hz), 3.77 (2H, t, J=5.6 Hz), 7.24 (1H, s), 7.44(1H, s).

Reference Example 223 tert-Butyl2-(2-chlorophenyl)ethyl[5-(1-methyl-2,2-dioxide-5,6-dihydro-1H,4H-[1,2,5]thiadiazolo[4,3,2-ij]quinoline-8-yl)-5-oxopentyl]carbamate

Using5-chloro-1-(1-methyl-2,2-dioxide-5,6-dihydro-1H,4H-[1,2,5]thiadiazolo[4,3,2-ij]quinolin-8-yl)-1-pentanoneobtained in Reference Example 222 and 2-(2-chlorophenyl)ethylamineaccording to the same method as that of Reference Example 19, the titlecompound was obtained as a pale yellow oil.

¹H NMR (200 MHz, CDCl₃) δ 1.42 (9H, br), 1.53–1.71 (4H, m), 2.19 (2H,quintet, J=5.6 Hz), 2.81 (2H, t, J=6.2 Hz), 2.94 (4H, m), 3.22 (2H, m),3.31 (3H, s), 3.41 (2H, t, J=6.8 Hz), 3.75 (2H, t, J=5.6 Hz), 7.15–7.35(5H, m), 7.44 (1H, s).

Reference Example 2245-Chloro-1-(2,2-dioxide-5,6-dihydro-1H,4H-[1,2,5]thiadiazolo[4,3,2-ij]quinolin-8-yl)-1-pentanone

Using 5,6-dihydro-1H,4H-[1,2,5]thiadiazolo[4,3,2-ij]quinoline2,2-dioxide and 5-chlorovaleryl chloride according to the same method asthat of Reference Example 1, the title compound was obtained as pale redcrystals having a melting point of 118 to 119° C.

¹H NMR (200 MHz, DMSO-d₆) δ 1.74 (4H, m), 2.06 (2H, t, J=6.0 Hz), 2.77(2H, t, J=5.8 Hz), 2.99 (2H, t, J=7.0 Hz), 3.65 (4H, m), 7.24 (1H, s),7.53 (1H, s), 11.58 (1H, s).

Reference Example 225 3,4-Dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide

Using 2-aminobenzylamine according to the same method as that ofReference Example 126, the title compound was obtained as pale yellowcrystals having a melting point of 178 to 180° C.

¹H NMR (200 MHz, DMSO-d₆) δ 4.40 (2H, d, J=7.8 Hz), 6.71 (1H, d, J=7.0Hz), 6.92 (1H, t, J=7.2 Hz), 7.11–7.32 (3H, m), 10.16 (1H, s).

Reference Example 2265-Chloro-1-(2,2-dioxide-3,4-dihydro-1H-2,1,3-benzothiadiazin-6-yl)-1-pentanone

Using 3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide obtained inReference Example 225 and 5-chlorovaleryl chloride according to the samemethod as that of Reference Example 1, the title compound was obtainedas colorless crystals having a melting point of 116 to 117° C.

¹H NMR (200 MHz, DMSO-d₆) δ 1.74 (4H, m), 2.98 (2H, t, J=6.6 Hz), 3.68(2H, t, J=6.2 Hz), 4.48 (2H, d, J=7.6 Hz), 6.78 (1H, d, J=8.8 Hz), 7.17(1H, m), 7.51 (1H, t, J=8.0 Hz), 7.83 (1H, s), 10.81 (1H, s).

Reference Example 227 1,3-Dimethyl-3,4-dihydro-1H-2,1,3-benzothiadiazine2,2-dioxide

Using 3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide obtained inReference Example 225 according to the same method as that of ReferenceExample 127, the title compound was obtained as colorless crystalshaving a melting point of 59 to 60° C.

¹H NMR (200 MHz, CDCl₃) δ 2.77 (3H, s), 3.34 (3H, s), 4.62 (2H, s), 6.90(1H, d, J=7.6 Hz), 7.04 (2H, m), 7.30 (1H, d, J=9.4 Hz).

Reference Example 2285-Chloro-1-(1,3-dimethyl-2,2-dioxide-3,4-dihydro-1H-2,1,3-benzothiadiazin-6-yl)-1-pentanone

Using 1,3-dimethyl-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxideobtained in Reference Example 227 and 5-chlorovaleryl chloride accordingto the same method as that of Reference Example 1, the title compoundwas obtained as colorless crystals having a melting point of 78 to 79°C.

¹H NMR (200 MHz, DMSO-d₆) δ 1.75 (4H, m), 2.67 (3H, s), 3.03 (2H, t,J=5.4 Hz), 3.32 (3H, s), 3.69 (2H, t, J=5.4 Hz), 4.74 (2H, s), 7.15 (1H,d, J=8.8 Hz), 7.84 (1H, s), 7.95 (1H, d, J=8.8 Hz).

Reference Example 229 2-Methyl-1,3-dioxo-5-isoindolinecarboxylic acid

An aqueous methyl amine solution (50 ml) was added to a solution oftrimellitic anhydride (30 g) in tetrahydrofuran (100 ml) After stirredat room temperature for 15 hours, the solvent was evaporated by heatingunder a normal pressure 1N hydrochloric acid was added-to the residue toadjust to pH 1, the precipitates were filtered, and washed successivelywith water, ethanol and diethyl ether Further air-drying afforded thetitle compound as colorless crystals (11.6 g) having a melting point of226 to 232° C.

¹H NMR (200 MHz, DMSO-d₆) δ 3.06 (3H, s), 7.97 (1H, d, J=7.6 Hz), 8.19(1H, s), 8.33 (1H, dd, J=7.7, 1.6 Hz), 8.00–10.00 (1H, br).

Reference Example 230 2-Methyl-1,3-dioxo-5-isoindolinecarbonyl chloride

Oxalyl chloride (5.86 ml) was added by portions to a solution of2-methyl-1,3-dioxo-5-isoindolinecarboxylic acid (9.2 g) obtained inReference Example 229 and dimethylformamide (catalytic amount) intetrahydrofuran (100 ml) at room temperature. After stirred at roomtemperature for 1 hour, the solvent was evaporated under reducedpressure. The resulting residue was filtered, washed with diethyl etherand dried under reduced pressure to give the title compound as a whitesolid.

¹H NMR (200 MHz, DMSO-d₆) δ 3.06 (3H, s), 7.97 (1H, d, J=7.6 Hz), 8.19(1H, s), 8.33 (1H, dd, J=7.9, 1.0 Hz).

Reference Example 2315-(5-Chloropentanoyl)-2-methyl-1H-isoindole-1,3(2H)-dione

Synthesis of the present compound was carried out according to themethod of Y. Tamaru et al. (Tetrahedron Lett. 1985, 26(45), 5529). Thatis, a solution of Zn—Cu couple (4.6 g) and 1-chloro-4-iodobutane (10.0g) in toluene (60 ml) and dimethylfomamide (6 ml) was stirred at 60° C.for 3 hours under nitrogen atmosphere. Then, a suspension of2-methyl-1,3-dioxo-5-isoindolinecarbonyl chloride (6.82 g) obtained inReference Example 230 and tetrakistriphenylphosphinepalladium (1.4 g) intoluene (30 ml) was added to the aforementioned solution at roomtemperature. After stirring at room temperature for 1 hour, the reactionwas quenched with water, and the solvent was evaporated under reducedpressure. Water was added to the residue, extracted with ethyl acetate,and washed successively with 1N hydrochloric acid, water, aqueouspotassium carbonate, water and saturated brine. The organic layer wasdried over anhydrous magnesium sulfate, and the solvent was evaporatedunder reduced pressure to give the title compound as colorless crystals(5.15 g) having a melting point of 97 to 98° C.

¹H NMR (200 MHz, DMSO-d₆) δ 1.65–1.90 (4H, m), 3.06 (3H, s), 3.22 (2H,t, J=6.8 Hz), 3.71 (2H, t, J=6.2 Hz), 7.98 (1H, d, J=7.6 Hz), 8.25–8.40(2H, m).

Reference Example 232N-[5-(5-chloropentanoyl)-2,3-dihydro-1H-inden-2-yl]-acetamide

Using N-(2,3-dihydro-1H-inden-2-yl)acetamide and 5-chlorovalerylchloride according to the same method as that of Reference Example 1,the title compound was obtained as colorless crystals having a melting,point of 106 to 108° C.

¹H NMR (200 MHz, DMSO-d₆) δ 1.75 (4H, m), 1.79 (3H, s), 2.77 (2H, dd,J=10.8, 3.0 Hz), 3.04 (2H, t, J=6.6 Hz), 3.21 (2H, dd, J=11.2, 5.2 Hz),3.69 (2H, t, J=6.3 Hz), 4.46 (1H, m), 7.35 (1H, d, J=7.6 Hz), 7.80 (2H,m), 8.16 (1H, d, J=5.4 Hz).

Reference Example 233N-[5-(5-chloropentanoyl)-2,3-dihydro-1H-inden-2-yl]methanesulfonamide

Using N-(2,3-dihydro-1H-inden-2-yl)methanesulfonamide and5-chlorovaleryl chloride according to the same method as that ofReference Example 1, the title compound was obtained as colorlesscrystals having a melting point of 71 to 72° C.

¹H NMR (200 MHz, DMSO-d₆) δ 1.86 (4H, m), 2.96 (4H, m), 3.01 (3H, s),3.35 (2H, dd, J=10.8, 4.6 Hz), 3.58 (2H, t, J=4.2 Hz), 4.29 (1H, m),5.21 (1H, m), 7.27 (1H, d, J=5.4 Hz), 7.79 (2H, m).

Reference Example 2345-(5-Chloropentanoyl)-1,3-dimethyl-1,3-dihydro-2H-benzimidazol-2-one(compound of Reference Example 10)

25.00 g Of 1,3-dimethyl-1,3-dihydro-2H-benzimidazol-2-one was dissolvedin 250 mL of acetonitrile, and 25.9 mL (1.3 equivalent) of5-chlorovaleryl chloride and 4.20 g, (0.2 equivalent) of zinc chloridewere added. After stirring at 80° C. for 6 hours, the reaction mixturewas concentrated under reduced pressure 250 mL of Ethyl acetate and 250mL of water were added, and the layers were separated. The organic layerwas washed with 125 mL of water two times, and concentrated underreduced pressure to give 53.16 g of pale yellow brown crystals 125 mL ofethanol was added, and warmed to 55° C. to dissolve crystals. 375 mL ofdiisopropyl ether was added dropwise to crystallize the material, whichwas cooled to 25° C., and stirred at the same temperature for 1 hour.After cooling to 5° C. or lower and stirring for 1 hour, crystals werecollected by filtration. Crystals were washed with 125 mL of coldethanol-diisopropyl ether (1:3), and dried under reduced pressure togive 27.16 g of the title compound as fine yellow brown crystals.

Reference Example 235 tert-Butyl2-(2-chlorophenyl)ethyl[5-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-5-hydroxypentyl]carbamate

95 mg of Sodium tetrahydroborate was added to a solution of tert-butyl2-(2-chlorophenyl)ethyl[5-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-5-oxopentyl]carbamateobtained in Reference Example 60 in methanol (10 ml) at roomtemperature. After stirring at room temperature for 2 hours, 20 ml of anaqueous saturated ammonium chloride solution was added. The liberatedoil was extracted with chloroform (30 ml×2), dried over anhydrousmagnesium sulfate, and the solvent was evaporated under reduced pressureto give the title compound as a pale yellow oil (1.25 g).

¹H NMR (400 MHz, CDCl₃) δ 1.21–1.52 (4H, m), 1.40 (9H, s), 1.63–1.90(2H, m), 2.92 (2H, br.s), 3.08–3.23 (2H, m), 3.31–3.41 (2H, m), 3.36(6H, s), 4.68 (1H, br.s), 5.10–5.18 (1H, m), 6.85 (1H, d, J=8.1 Hz),6.96 (1H, m), 7.02 (1H, d, J=8.1 Hz), 7.16–7.34 (4H, m).

Reference Example 236 tert-Butyl2-(2-chloro-4-hydroxyphenyl)ethyl[5-oxo-5-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)pentyl]carbamate

Using8-(5-chloropentanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(584 mg) obtained in Reference Example 1 and4-(2-aminoethyl)-3-chlorophenol hydrobromide (1.1 g) according to thesame method as that of Reference Example 82, the title compound wasobtained as a pale yellow oil (250 mg).

¹H NMR (400 MHz, CDCl₃) δ 1.41 (9H, s), 1.51–1.73 (4H, m), 2.72 (2H, t,J=7.5 Hz), 2.85 (2H, br.s), 2.92 (2H, t, J=6.8 Hz), 3.01 (2H, t, J=7.5Hz), 3.15–3.24 (4H, m), 3.36 (2H, br.s), 4.13 (2H, t, J=8.3 Hz), 6.69(1H, d, J=7.0 Hz), 6.89–7.07 (3H,r m), 7.66 (1H, s), 7.71 (1H, s).

Reference Example 237 tert-Butyl5-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-oxopentyl[2-(2-chloro-4-hydroxyphenyl)ethyl]carbamate

Using 1-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-5-chloropentan-1-one (560mg) obtained in Reference Example 11 and4-(2-aminoethyl)-3-chlorophenol-hydrobromide (1.1 g) according to thesame method as that of Reference Example 82, the title compound wasobtained as a pale yellow oil (320 mg).

¹H NMR (400 MHz, CDCl₃) δ 1.41 (9H, s), 1.51–1.72 (4H, m), 2.26 (3H, s),2.85 (2H, br.s), 2.95 (2H, t, J=7.3 Hz), 3.15 (2H, br.s), 3.23 (2H, t,J=8.0 Hz), 3.36 (2H, t, J=7.0 Hz), 4.11 (2H, t, J=7.0 Hz), 6.69 (1H, d,J=6.3 Hz), 6.90–7.07 (3H, m), 7.80 (1H, s), 7.81 (1H, d, J=8.0 Hz), 8.22(1H, d, J=8.0 Hz).

Reference Example 238 tert-Butyl2-(2-chloro-4-hydroxyphenyl)ethyl[5-(1-methyl-2-oxo-1,2,5,6-tetrahydro-4H-imidazo[4,5,1-ij]quinolin-8-yl)-5-oxopentyl]carbamate

Using8-(5-chloropentanoyl)-1-methyl-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2-(1H)-one(460 mg) obtained in Reference Example 134 and4-(2-aminoethyl)-3-chlorophenol hydrobromide (796 mg) according to thesame method as that of Reference Example 82, the title compound wasobtained as a pale yellow oil (114 mg).

¹H NMR (400 MHz, CDCl₃) δ 1.40 (9H, s), 1.60 (2H, br.s), 1.66–1.75 (2H,m), 2.10–2.16 (2H, m), 2.84–3.00 (6H, m), 3.16–3.22 (2H, m), 3.31–3.38(2H, m), 3.45 (3H, s), 3.82–3.89 (2H,m), 6.70 (1H, d, J=7.8 Hz),6.83–7.02 (2H, m), 7.23 (1H, br.), 7.49 (1H, s), 7.56 (1H, s).

Reference Example 239 tert-Butyl2-(2-chloro-4-hydroxyphenyl)ethyl[5-oxo-5-(2-oxo-1,2,5,6-tetrahydro-4H-imidazo[4,5,1-ij]quinolin-8-yl)pentyl]carbamate

Using8-(5-chloropentanoyl)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one(439 mg) obtained in Reference Example 133 and4-(2-aminoethyl)-3-chlorophenol hydrobromide (796 mg) according to thesame method as that of Reference Example 82, the title compound wasobtained as a pale yellow oil (55 mg).

¹H NMR (400 MHz, CDCl₃) δ 1.43 (9H, s), 1.49–1.72 (4H, m), 2.13 (2H,br.s), 2.83–2.89 (6H, m), 3.08 (2H, br.s), 3.35 (2H, t, J=6.8 Hz), 3.88(2H, br.s), 6.88–7.02 (3H, m), 7.51 (1H, s), 7.56 (1H, br.s), 8.09 (1H,br), 9.95 (1H, s).

Reference Example 240 tert-Butyl2-(2-chloro-4-hydroxyphenyl)ethyl[5-oxo-5-(2-oxo-1,2,5,6-tetrahydro-4H-imidazo[4,5,1-ij]quinolin-9-yl)pentyl]carbamate

Using 5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one obtained inReference Example 131 according to the same method as those of ReferenceExample 1 and Reference Example 82, the title compound was obtained as apale yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 1.43 (9H, s), 1.56 (2H, br.s), 1.68 (2H,br.s), 2.09–2.16 (2H, m), 2.84–2.90 (4H, m), 2.95 (2H, t, J=7.0 Hz),3.13 (2H, t, J=7.3 Hz), 3.35 (2H, t, J=7.0 Hz), 3.87 (2H, t, J=6.0 Hz),6.88–7.04 (4H, m), 7.44 (1H, d, J=8.0 Hz), 7.89 (1H, br.), 9.34 (1H, s).

Reference Example 241N-[5-(5-chloropentanoyl)-2,3-dihydro-1H-inden-2-yl]acetamide

Using N-(2,3-dihydro-1H-inden-2-yl)-N-methylacetamide and5-chlorovaleryl chloride according to the same method as that of Example1, the title compound was obtained as colorless crystals.

¹H NMR (200 MHz, CDCl₃) δ 1.81 (4H, m), 2.20 (3H, s), 2.41 (2H, m), 2.79(3H, s), 3.06 (2H, t, J=6.6 Hz), 3.18–3.22 (2H, m), 3.59 (2H, t, J=6.3Hz), 5.46 (1H, m), 7.30 (1H, m), 7.81 (2H, m).

Reference Example 242N-[5-(5-chloropentanoyl)-2,3-dihydro-1H-inden-2-yl]methanesulfonamide

Using N-(2,3-dihydro-1H-inden-2-yl)methanesulfonamide, and5-chlorovaleryl chloride according to the same method as that of Example1, the title compound was obtained as colorless crystals.

MS m/z: 344 [M+H]⁺

Example 18-[5-[(2-Phenylethyl)amino]pentanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

A 4N hydrogen chloride-ethyl acetate solution was added to a solution oftert-butyl5-oxo-5-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)pentyl(2-phenylethyl)carbamate(3.00 g) obtained in Reference Example 19 in ethanol (5 ml), and themixture was stirred at room temperature for 1 hour. The solvent wasevaporated under reduced pressure, and the resulting residue wascrystallized from ethanol-ethyl acetate to give the title compound ascolorless crystals (1.98 g) having a melting point of 166 to 168° C.

¹H NMR(300 MHz, DMSO-d₆) δ 1.60–1.75 (4H, m), 2.59 (2H, t, J=7.6 Hz),2.90–3.20 (10H, m), 3.18 (2H, t, J=8.4 Hz), 3.99 (2H, t, J=8.4 Hz),7.20–7.40 (5H, m), 7.73 (1H, s), 7.74 (1H, s), 8.95–9.10 (2H, br).elementary analysis as C₂₄H₂₈N₂O₂.HCl calculation value: C, 69.80; H,7.08; N, 6.78. experimental value: C, 69.43; H, 7.06; N, 6.72.

Example 28-(5-[[2-(2-Methoxyphenyl)ethyl]amino]pentanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using tert-butyl2-(2-methoxyphenyl)ethyl[5-oxo-5-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)pentyl]carbamate(1.16 g) obtained in Reference Example 20 according to the same methodas that of Example 1, the title compound (835 mg) was obtained ascolorless crystals having a melting point of 94 to 96° C.

¹H NMR(200 MHz, DMSO-d₆) δ 1.60–1.80 (4H, m), 2.59 (2H, t, J=7.6 Hz),2.85–3.15 (10H, m), 3.18 (2H, t, J=8.4 Hz), 3.80 (3H, s), 3.99 (2H, t,J=8.4 Hz), 6.91 (1H, dt, J=7.3, 1.0 Hz), 7.00 (1H, d, J=7.6 Hz),7.15–7.30 (2H, m), 7.74 (2H, s), 8.95–9.15 (2H, br). elementary analysisas C₂₅H₃₀N₂O₃.HCl.H₂O calculation value: C, 62.69; H, 7.36; N, 5.85.experimental value: C, 63.02; H, 7.15; N, 5.82.

Example 38-(5-[[2-(3-Methoxyphenyl)ethyl]amino]pentanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using tert-butyl2-(3-methoxyphenyl)ethyl[5-oxo-5-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)pentyl]carbamate(3.02 g) obtained in Reference Example 21 according to the same methodas that of Example 1, the title compound (2.32 g) was obtained ascolorless crystals having a melting point of 97 to 100° C.

¹H NMR(200 MHz, DMSO-d₆) δ 1.55–1.80 (4H, m), 2.59 (2H, t, J=7.6 Hz),2.85–3.20 (10H, m), 3.17 (2H, t, J=8.4 Hz), 3.75 (3H, s), 3.99 (2H, t,J=8.4 Hz), 6.75–6.85 (3H, m), 7.25 (1H, t, J=8.2 Hz), 7.74 (2H, s),9.15–9.35 (2H, br). elementary analysis as C₂₅H₃₀N₂O₃.HCl.1.5H₂Ocalculation value: C, 63.89; H, 7.29; N, 5.96. experimental value: C,64.01; H, 7.01; N, 6.01.

Example 4 8-(5-[[2-(3,4-Dimethoxyphenyl)ethyl]amino]pentanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using tert-butyl2-(3,4-dimethoxyphenyl)ethyl[5-oxo-5-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)pentyl]carbamate(408 mg) obtained in Reference Example 22 according to the same methodas that of Example 1, the title compound (290 mg) was obtained ascolorless crystals having a melting point of 175 to 176° C.

¹H NMR(200 MHz, DMSO-d₆) δ 1.55–1.80 (4H, m), 2.59 (2H, t, J=7.6 Hz),2.80–3.20 (10H, m), 3.18 (2H, t, J=8.4 Hz), 3.72 (3H, s), 3.75 (3H, s),3.99 (2H, t, J=8.4 Hz), 6.76 (1H, dd, J=8.2, 1.8 Hz), 6.90 (2H, d, J=8.2Hz), 7.73 (2H, s), 8.85–9.05 (2H, br).

Example 58-(5-[[2-(2-Chlorophenyl)ethyl]amino]pentanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using2-(2-chlorophenyl)ethyl[5-oxo-5-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)pentyl]carbamate(1.50 g) obtained in Reference Example 23 according to the same methodas that of Example 1, the title compound (989 mg) was obtained ascolorless crystals having a melting point of 128 to 130° C.

¹H NMR(200 MHz, DMSO-d₆) δ 1.55–1.80 (4H, m), 2.59 (2H, t, J=7.6 Hz),2.90–3.25 (12H, m), 3.99 (2H, t, J=8.4 Hz), 7.00–7.55 (4H, m), 7.73 (2H,s), 9.10–9.30 (2H, br). elementary analysis as C₂₄H₂₇ClN₂O₂.HCl.H₂Ocalculation value: C, 60.76; H, 6.59; N, 5.90. experimental value: C,61.15; H, 6.20; N, 5.77.

Example 68-(5-[[2-(3-Fluorophenyl)ethyl]amino]pentanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using 2-(3-fluorophenyl)ethyl[5-oxo-5-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)pentyl]carbamate(1.40 g) obtained in Reference Example 24 according to the same methodas that of Example 1, the title compound (905 mg) was obtained ascolorless crystals having a melting point of 172, to 173° C.

¹H NMR(200 MHz, DMSO-d₆) δ 1.55–1.80 (4H, m), 2.59; (2H, t, J=7.6 Hz),2.85–3.25 (12H, m), 3.99 (2H, t, J=8.4 Hz), 7.00–7.20 (3H, m), 7.50–7.65(1H, m), 7.74 (2H, s), 8.90–9.10 (2H, br). elementary analysis asC₂₄H₂₇FN₂O₂.HCl calculation value: C, 66.89; H, 6.55; N, 6.50.experimental value: C, 66.50; H, 6.21; N, 6.20.

Example 72-Methoxy-5-(2-[[5-oxo-5-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)pentyl]amino]ethyl)benzenesulfonamidehydrochloride

Using tert-butyl2-[3-(aminosulfonyl)-4-methoxyphenyl]ethyl[5-oxo-5-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)pentyl]carbamate(605 mg) obtained in Reference Example 25 according to the same methodas that of Example 1, the title compound (325 mg) was obtained ascolorless crystals having a melting point of 145° C. (dec).

¹H NMR(200 MHz, DMSO-d₆) δ 1.55–1.75 (4H, m), 2.60 (2H, t, J=7.6 Hz),2.85–3.20 (10H, m), 3.18 (2H, t, J=8.4 Hz), 3.89 (3H, s), 3.99 (2H, t,J=8.4 Hz), 7.08 (2H, s), 7.18 (1H, d, J=8.8 Hz), 7.47 (1H, dd, J=8.6,2.2 Hz), 7.63 (1H, d, J=2.2 Hz), 7.74 (2H, s), 8.85–9.05 (2H, br).elementary analysis as C₂₅H₃₁N₃O₅S.HCl.H₂O calculation value: C, 55.60;H, 6.35; N, 7.78. experimental value: C, 55.51; H, 6.50; N, 7.46.

Example 88-(5-[[2-(2-Methoxyphenyl)-1-methylethyl]amino]pentanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using tert-butyl2-(2-methoxyphenyl)-1-methylethyl[5-oxo-5-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)pentyl]carbamate(641 mg) obtained in Reference Example 26 according to the same methodas that of Example 1, the title compound (438 mg) was obtained as paleyellow a morphous powders.

¹H NMR(200 MHz, DMSO-d₆) δ 1.10 (3H, d, J=6.2 Hz), 1.60–1.90 (4H, m),2.59 (2H, t, J=7.6 Hz), 2.80–3.20 (9H, m), 3.18 (2H, t, J=8.4 Hz), 3.80(3H, s), 3.99 (2H, t, J=8.4 Hz), 6.80–7.60 (4H, m), 7.73 (2H, s),8.90–9.25 (2H, br). elementary analysis as C₂₆H₃₂N₂O₃.HCl.H₂Ocalculation value: C, 65.74; H, 7.43; N, 5.90. experimental value: C,65.44; H, 7.09; N, 5.72.

Example 98-[5-[Methyl(2-phenylethyl)amino]pentanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

A mixed solution of8-(5-chloropentanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(800 mg) obtained in Reference Example 1,N-methyl-N-(2-phenylethyl)amine (0.438 ml) and potassium carbonate (830mg) in toluene (10 ml) was heated under reflux for 12 hours withstirring. After cooling, water (15 ml) and ethyl acetate (20 ml) wereadded to the reaction mixture, and the mixture was extracted with ethylacetate. The extract was washed with brine, dried over anhydrousmagnesium sulfate, and the solvent was evaporated under reducedpressure. The resulting residue was purified by silica gelchromatography (eluting solvent; ethyl acetate) to give a free basecompound of the title compound as a pale yellow oil (519 mg).

¹H NMR(free base; 300 MHz, CDCl₃) δ 1.50–1.65 (2H, m), 1.74 (2H, tt,J=7.5, 7.5 Hz), 2.31 (3H, s), 2.45 (2H, t, J=7.5 Hz), 2.55–2.65 (2H, m),2.65–2.80 (4H, m), 2.92 (2H, t, J=7.5 Hz), 3.01 (2H, t, j=8.1 Hz), 3.21(2H, t, J=8.1 Hz), 4.12 (2H, t, J=8.4 Hz), 7.15–7.30 (5H, m), 7.67 (1H,s), 7.72 (1H, s).

A solution of the free base compound (519 mg) in ethanol was treatedwith 1 equivalent or more of hydrogen chloride (ethyl acetate solution)to give the title compound as pale yellow amorphous powders (539 mg).elementary analysis as C₂₅H₃₀N₂O₂.HCl calculation value: C, 70.32; H,7.32; N, 6.56. experimental value: C, 70.04; H, 7.56; N, 6.59.

Example 108-[5-[[2-(2-Methoxyphenyl)ethyl](methyl)amino]pentanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using8-(5-chloropentanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(500 mg) obtained in Reference Example 1 andN-[2-(2-methoxyphenyl)ethyl]-N-methylamine (322 mg) according to thesame method as that of Example 9, the title compound (280 mg) wasobtained as pale yellow amorphous powders.

¹H NMR(free base; 300 MHz, CDCl₃) δ 1.50–1.65 (2H, m), 1.75 (2H, tt,J=7.5, 7.5 Hz), 2.32 (3H, s), 2.47 (2H, t, J=7.5 Hz), 2.50–2.60 (2H, m),2.65–2.80 (4H, m), 2.93 (2H, t, J=7.5 Hz), 3.02 (2H, t, J=8.1 Hz), 3.22(2H, t, J=8.1 Hz), 3.81 (3H, s), 4.13 (2H, t, J=8.4 Hz), 6.84 (1H, d,J=7.5 Hz), 6.88 (1H, d, J=7.8 Hz), 7.10–7.20 (2H, m), 7.68 (1H, s), 7.72(1H, s). elementary analysis as C₂₆H₃₂N₂O₃.HCl.0.5H₂O calculation value:C, 67.01; H, 7.35; N, 6.01. experimental value: C, 67.03; H, 7.68; N,5.97.

Example 118-[5-[[2-(3-Methoxyphenyl)ethyl](methyl)amino]pentanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using8-(5-chloropentanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(500 mg) obtained in Reference Example 1 andN-[2-(3-methoxyphenyl)ethyl]-N-methylamine (322 mg) according to thesame method as that of Example 9, the title compound (160 mg) wasobtained as pale yellow amorphous powders.

¹H NMR(free base; 300 MHz, CDCl₃) δ 1.50–1.65 (2H, m), 1.75 (2H, tt,J=7.5, 7.5 Hz), 2.30 (3H, s), 2.45 (2H, t, J=7.5 Hz), 2.55–2.65 (2H, m),2.65–2.80 (4H, m), 2.92 (2H, t, J=7.2 Hz), 3.01 (2H, t, J=7.8 Hz), 3.21(2H, t, J=8.1 Hz), 3.78 (3H, s), 4.12 (2H, t, J=8.4 Hz), 6.70–6.80 (3H,m), 7.16 (1H, t, J=7.8 Hz), 7.67 (1H, s), 7.72 (1H, s).

Example 128-[5-[[2-(2-Chlorophenyl)ethyl](methyl)amino]pentanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using8-(5-chloropentanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(500 mg) obtained in Reference Example 1 andN-[2-(2-chlorophenyl)ethyl]-N-methylamine (330 mg) according to the samemethod as that of Example 9, the title compound (310 mg) was obtained aspale yellow amorphous powders.

¹H NMR(free base; 300 MHz, CDCl₃) δ 1.50–1.65 (2H, m), 1.74 (2H, tt,J=7.5, 7.5 Hz), 2.34 (3H, s), 2.47 (2H, t, J=7.5 Hz), 2.55–2.65 (2H, m),2.71 (2H, t, J=7.5 Hz), 2.85–2.95 (4H, m), 3.02 (2H, t, J=7.8 Hz), 3.22(2H, t, J=8.1 Hz), 4.13 (2H, t, J=8.4 Hz), 7.05–7.35 (4H, m), 7.68 (1H,s), 7.72 (1H, s).

Example 138-[5-[[2-(3-Chlorophenyl)ethyl](methyl)amino]pentanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using8-(5-chloropentanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(500 mg) obtained in Reference Example 1 andN-[2-(3-chlorophenyl)ethyl]-N-methylamine (345 mg) according to the samemethod as that of Example 9, the title compound (298 mg) was obtained aspale yellow amorphous powders.

¹H NMR(free base; 200 MHz, CDCl₃) δ 1.50–1.65 (2H, m), 1.73 (2H, tt,J=7.4, 7.4 Hz), 2.29 (3H, s), 2.44 (2H, t, J=7.4 Hz), 2.50–2.80 (6H, m),2.92 (2H, t, J=7.2 Hz), 3.02 (2H, t, J=7.8 Hz), 3.22 (2H, t, J=8.4 Hz),4.13 (2H, t, J=8.4 Hz), 7.00–7.20 (4H, m), 7.67 (1H, s), 7.71 (1H, s).elementary analysis as C₂₅H₂₉ClN₂O₂.HCl.H₂O calculation value: C, 62.63;H, 6.73; N, 5.84. experimental value: C, 62.51; H, 6.53; N, 5.70.

Example 148-[5-[[2-(3-Fluorophenyl)ethyl](methyl)amino]pentanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using8-(5-chloropentanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(500 mg) obtained in Reference Example 1 andN-[2-(3-fluorophenyl)ethyl]-N-methylamine (276 mg) according to the samemethod as that of Example 9, the title compound (340 mg) was obtained aspale yellow amorphous powders.

¹H NMR(free base; 300 MHz, CDCl₃) δ 1.50–1.65 (2H, m), 1.74 (2H, tt,J=7.5, 7.5 Hz), 2.29 (3H, s), 2.44 (2H, t, J=7.5 Hz), 2.55–2.65 (2H, m),2.65–2.80 (4H, m), 2.92 (2H, t, J=7.5 Hz), 3.01 (2H, t, J=7.8 Hz), 3.22(2H, t, J=8.1 Hz), 4.12 (2H, t, J=8.4 Hz), 6.80–7.00 (3H, m), 7.15–7.25(1H, m), 7.67 (1H, s), 7.72 (1H, s). elementary analysis asC₂₅H₂₉FN₂O₂.HCl.0.5H₂O calculation value: C, 66.14; H, 6.88; N, 6.17.experimental value: C, 66.23; H, 6.38; N, 5.74.

Example 158-[5-[Ethyl(2-phenylethyl)amino]pentanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using8-(5-chloropentanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(500 mg) obtained in Reference Example 1 andN-ethyl-N-(2-phenylethyl)amine (281 mg) according to the same method asthat of Example 9, the title compound (230 mg) was obtained as paleyellow amorphous powders.

¹H NMR(free base; 300 MHz, CDCl₃) δ 1.06 (3H, t, J=7.2 Hz), 1.56 (2H,tt, J=7.5, 7.5 Hz), 1.73 (2H, tt, J=7.5, 7.5 Hz), 2.50–2.80 (10H, m),2.92 (2H, t, J=7.2 Hz), 3.01 (2H, t, J=7.8 Hz), 3.22 (2H, t, J=8.4 Hz),4.12 (2H, t, J=8.4 Hz), 7.10–7.30 (5H, m), 7.67 (1H, s), 7.72 (1H, s).elementary analysis as C₂₆H₃₂N₂O₂.HCl.0.5H₂O calculation value: C,69.39; H, 7.62; N, 6.23. experimental value: C, 69.50; H, 7.69; N, 6.17.

Example 168-(5-[Ethyl[2-(2-methoxyphenyl)ethyl]amino]pentanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using8-(5-chloropentanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(500 mg) obtained in Reference Example 1 andN-ethyl-N-[2-(2-methoxyphenyl)ethyl]amine (337 mg) according to the samemethod as that of Example 9, the title compound (300 mg) was obtained aspale yellow amorphous powders.

¹H NMR(free base; 300 MHz, CDCl₃) δ 1.07 (3H, t, J=7.2 Hz), 1.35–1.45(2H, m), 1.75 (2H, tt, J=7.5, 7.5 Hz), 2.50–2.80 (10H, m), 2.93 (2H, t,J=7.2 Hz), 3.02 (2H, t, J=7.8 Hz), 3.22 (2H, t, J=8.4 Hz), 3.81 (3H, s),4.13 (2H, t, J=8.4 Hz), 6.84 (1H, d, J=8.1 Hz), 6.88 (1H, d, J=7.2 Hz),7.10–7.20 (2H, m), 7.68 (1H, s), 7.73 (1H, s). elementary analysis asC₂₇H₃₄N₂O₃.HCl.H₂O calculation value: C, 66.31; H, 7.63; N, 5.73.experimental value: C, 66.58; H, 7.36; N, 5.49.

Example 178-(5-[Isopropyl[2-(2-methoxyphenyl)ethyl]amino]pentanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using8-(5-chloropentanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(700 mg) obtained in Reference Example 1 andN-isopropyl-N-[2-(2-methoxyphenyl)ethyl]amine (510 mg) according to thesame method as that of Example 9, the title compound (310 mg) wasobtained as pale yellow amorphous powders.

¹H NMR(free base; 300 MHz, CDCl₃) δ 1.00 (6H, d, J=6.6 Hz), 1.50–1.60(2H, m), 1.74 (2H, tt, J=7.4, 7.4 Hz), 2.51 (2H, t, J=7.5 Hz), 2.55–3.05(11H, m), 3.22 (2H, t, J=8.4 Hz), 3.81 (3H, s), 4.12 (2H, t, J=8.4 Hz),6.80–6.95 (2H, m), 7.10–7.20 (2H, m), 7.69 (1H, s), 7.73 (1H, s).

Example 188-[5-[[2-(2-Chlorophenyl)ethyl](isopropyl)amino]pentanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using8-(5-chloropentanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(700 mg) obtained in Reference Example 1 andN-[2-(2-chlorophenyl)ethyl]-N-isopropylamine (522 mg) according to thesame method as that of Example 9, the title compound (70 mg) wasobtained as pale yellow amorphous powders.

¹H NMR(free base; 300 MHz, CDCl₃) δ 1.00 (6H, d, J=6.6 Hz), 1.50–1.60(2H, m), 1.73 (2H, tt, J=7.4, 7.4 Hz), 2.51 (2H, t, J=7.5 Hz), 2.55–2.65(2H, m), 2.71 (2H, t, J=7.5 Hz), 2.80–3.05 (5H, m), 3.22 (2H, t, J=8.4Hz), 4.13 (2H, t, J=8.4 Hz), 7.05–7.40 (4H, m), 7.68 (1H, s), 7.72 (1H,s).

Example 198-[6-[(2-Phenylethyl)amino]hexanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using tert-butyl6-oxo-6-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)hexyl(2-phenylethyl)carbamate(450 mg) obtained in Reference Example 27 according to the same methodas that of Example 1, the title compound (283 mg) was obtained ascolorless crystals having a melting point of 144 to 146° C.

¹H NMR(200 MHz, DMSO-d₆) δ 1.25–1.45 (2H, m), 1.55–1.80 (4H, m), 2.59(2H, t, J=7.6 Hz), 2.80–3.25 (12H, m), 3.99 (2H, t, J=8.4 Hz), 7.20–7.40(5H, m), 7.73 (2H, s), 8.90–9.10 (2H, br).

Example 208-(6-[[2-(2-Methoxyphenyl)ethyl]amino]hexanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using tert-butyl2-(2-methoxyphenyl)ethyl[6-oxo-6-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)hexyl]carbamate(1.51 g) obtained in Reference Example 28 according to the same methodas that of Example 1, the title compound (1.04 g) was obtained ascolorless crystals having a melting point of 105 to 107° C.

¹H NMR(300 MHz, DMSO-d₆) δ 1.30–1.45 (2H, m), 1.55–1.75 (4H, m), 2.59(2H, t, J=7.6 Hz), 2.85–3.10 (10H, m), 3.17 (2H, t, J=8.4 Hz), 3.80 (3H,s), 3.99 (2H, t, J=8.4 Hz), 6.91 (1H, t, J=7.5 Hz), 7.00 (1H, d, J=8.4Hz), 7.15–7.30 (2H, m), 7.73 (2H, s), 8.75–9.00 (2H, br). elementaryanalysis as C₂₆H₃₂N₂O₃.HCl.H₂O calculation value: C, 65.74; H, 7.43; N,5.90. experimental value: C, 66.09; H, 7.01; N, 5.80.

Example 218-(6-[[2-(3-Methoxyphenyl)ethyl]amino]hexanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using tert-butyl2-(3-methoxyphenyl)ethyl[6-oxo-6-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)hexyl]carbamate(562 mg) obtained in Reference Example 29 according to the same methodas that of Example 1, the title compound (435 mg) was obtained ascolorless crystals having a melting point of 136 to 138° C.

¹H NMR(200 MHz, DMSO-d₆) δ 1.25–1.45 (2H, m), 1.55–1.80 (4H, m), 2.59(2H, t, J=7.6 Hz), 2.85–3.25 (12H, m), 3.75 (3H, s), 3.99 (2H, t, J=8.4Hz), 6.80–6.85 (3H, m), 7.25 (1H, t, J=7.8 Hz), 7.73 (2H, s), 9.00–9.20(2H, br). elementary analysis as C₂₆H₃₂N₂O₃.HCl.H₂O calculation value:C, 65.74; H, 7.43; N, 5.90. experimental value: C, 65.54; H, 7.28; N,5.80.

Example 228-(6-[[2-(4-Methoxyphenyl)ethyl]amino]hexanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using tert-butyl2-(4-methoxyphenyl)ethyl[6-oxo-6-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)hexyl]carbamate(900 mg) obtained in Reference Example 30 according to the same methodas that of Example 1, the title compound (707 mg) was obtained ascolorless crystals having a melting point of 179 to 180° C.

¹H NMR(300 MHz, DMSO-d₆) δ 1.25–1.45 (2H, m), 1.55–1.75 (4H, m), 2.59(2H, t, J=7.5 Hz), 2.80–3.10 (10H, m), 3.17 (2H, t, J=8.4 Hz), 3.73 (3H,s), 3.98 (2H, t, J=8.4 Hz), 6.89 (2H, d, J=7.5 Hz), 7.18 (2H, d, J=7.5Hz), 7.73 (2H, s), 8.90–9.10 (2H, br). elementary analysis asC₂₆H₃₂N₂O₃.HCl.0.5H₂O calculation value: C, 67.01; H, 7.35; N, 6.01.experimental value: C, 67.53; H, 7.40; N, 6.03.

Example 238-(6-[[2-(2-Chlorophenyl)ethyl]amino]hexanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using tert-butyl2-(2-chlorophenyl)ethyl[6-oxo-6-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)hexyl]carbamate(540 mg) obtained in Reference Example 31 according to the same methodas that of Example 1, the title compound (368 mg) was obtained ascolorless crystals having a melting point of 172 to 174° C.

¹H NMR(200 MHz, DMSO-d₆) δ 1.25–1.45 (2H, m), 1.55–1.80 (4H, m), 2.59(2H, t, J=7.6 Hz), 2.85–3.25 (12H, m), 3.99 (2H, t, J=8.4 Hz), 7.25–7.50(4H, m), 7.73 (2H, s), 9.05–9.30 (2H, br). elementary analysis asC₂₅H₂₉ClN₂O₂.HCl.0.5H₂O calculation value: C, 63.83; H, 6.64; N, 5.95.experimental value: C, 63.68; H, 6.57; N, 5.80.

Example 248-(6-[[2-(3-Fluorophenyl)ethyl]amino]hexanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using tert-butyl2-(3-fluorophenyl)ethyl[6-oxo-6-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)hexyl]carbamate(613 mg) obtained in Reference Example 32 according to the same methodas that of Example 1, the title compound (493 mg) was obtained ascolorless crystals having a melting point of 182 to 184° C.

¹H NMR (200 MHz, DMSO-d₆) δ 1.25–1.45 (2H, m), 1.55–1.80 (4H, m), 2.59(2H, t, J=7.6 Hz), 2.85–3.25 (12H, m), 3.99 (2H, t, J=8.4 Hz), 7.00–7.20(3H, m), 7.30–7.45 (1H, m), 7.73 (2H, s), 9.00–9.20 (2H, br).

Example 258-(6-[[2-(2-Methoxyphenyl)-1-methylethyl]amino]hexanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using tert-butyl2-(2-methoxyphenyl)-1-methylethyl[6-oxo-6-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)hexyl]carbamate(467 mg) obtained in Reference Example 33 according to the same methodas that of Example 1, the title compound (348 mg) was obtained as paleyellow amorphous powders.

¹H NMR(300 MHz, DMSO-d₆) δ 1.10 (3H, d, J=6.3 Hz), 1.25–1.50 (2H, m),1.55–1.80 (4H, m), 2.59 (2H, t, J=7.5 Hz), 2.60–2.80 (1H, m), 2.80–3.40(10H, m), 3.80 (3H, s), 3.99 (2H, t, J=8.4 Hz), 6.91 (1H, t, J=7.2 Hz),7.00 (1H, d, J=8.4 Hz), 7.18 (1H, d, J=7.2 Hz), 7.26 (1H, t, J=8.4 Hz),7.74 (2H, s), 9.00–9.20 (2H, br). elementary analysis asC₂₇H₃₄N₂O₃.HCl.0.5H₂O calculation value: C, 67.55; H, 7.56; N, 5.84.experimental value: C, 67.40; H, 7.55; N, 5.63.

Example 268-[6-[Methyl(2-phenylethyl)amino]hexanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using8-(6-bromohexanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(650 mg) obtained in Reference Example 2 andN-methyl-N-(2-phenylethyl)amine (0.297 ml) according to the same methodas that of Example 9, the title compound (326 mg) was obtained ascolorless crystals having a melting point of 83 to 85° C.

¹H NMR(free base; 300 MHz, CDCl₃) δ 1.35–1.50 (2H, m), 1.56 (2H, tt,J=7.5, 7.5 Hz), 1.75 (2H, tt, J=7.5, 7.5 Hz), 2.32 (3H, s), 2.44 (2H, t,J=7.5 Hz), 2.55–2.65 (2H, m), 2.71 (2H, t, J=7.5 Hz), 2.75–2.85 (2H, m),2.91 (2H, t, J=7.2 Hz), 3.02 (2H, t, J=7.8 Hz), 3.22 (2H, t, J=8.4 Hz),4.12 (2H, t, J=8.4 Hz), 7.15–7.35 (5H, m), 7.67 (1H, s), 7.71 (1H, s).elementary analysis as C₂₆H₃₂N₂O₂.HCl.0.5H₂O calculation value: C,69.39; H, 7.62; N, 6.23. experimental value: C, 69.08; H, 7.41; N, 6.09.

Example 278-[6-[[2-(2-Methoxyphenyl)ethyl](methyl)amino]hexanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using8-(6-bromohexanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(500 mg) obtained in Reference Example 2 andN-[2-(2-methoxyphenyl)ethyl]-N-methylamine (282 mg) according to thesame method as that of Example 9, the title compound (100 mg) wasobtained as pale yellow amorphous powders.

¹H NMR(free base; 300 MHz, CDCl₃) δ 1.35–1.45 (2H, m), 1.50–1.60 (2H,m), 1.75 (2H, tt, J=7.5, 7.5 Hz), 2.32 (3H, s), 2.43 (2H, t, J=7.5 Hz),2.50–2.60 (2H, m), 2.71 (2H, t, J=7.5 Hz), 2.75–2.85 (2H, m), 2.91 (2H,t, J=7.2 Hz), 3.02 (2H, t, J=7.8 Hz), 3.22 (2H, t, J=8.4 Hz), 3.82 (3H,s), 4.13 (2H, t, J=8.4 Hz), 6.80–6.85 (2H, m), 7.10–7.20 (2H, m), 7.67(1H, s), 7.72 (1H, s).

Example 288-[6-[[2-(3-Methoxyphenyl)ethyl](methyl)amino]hexanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using8-(6-bromohexanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(500 mg) obtained in Reference Example 2 andN-[2-(3-methoxyphenyl)ethyl]-N-methylamine (282 mg) according to thesame method as that of Example 9, the title compound (528 mg) wasobtained as colorless crystals having a melting point of 116 to 118° C.

¹H NMR(free base; 300 MHz, CDCl₃) δ 1.30–1.45 (2H, m), 1.50–1.60 (2H,m), 1.74 (2H, tt, J=7.5, 7.5 Hz), 2.30 (3H, s), 2.42 (2H, t, J=7.5 Hz),2.55–2.80 (6H, m), 2.91 (2H, t, J=7.2 Hz), 3.01 (2H, t, J=7.8 Hz), 3.21(2H, t, J=8.4 Hz), 3.78 (3H, s), 4.11 (2H, t, J=8.4 Hz), 6.70–6.85 (3H,m), 7.18 (1H, dt, J=7.5, 0.9 Hz), 7.67 (1H, s), 7.71 (1H, s). elementaryanalysis as C₂₇H₃₄N₂O₃.HCl.H₂O calculation value: C, 66.31; H, 7.63; N,5.73. experimental value: C, 66.27; H, 7.49; N, 5.55.

Example 298-[6-[[2-(2-Chlorophenyl)ethyl](methyl)amino]hexanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using8-(6-bromohexanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(500 mg) obtained in Reference Example 2 andN-[2-(2-chlorophenyl)ethyl]-N-methylamine (288 mg) according to the samemethod as that of Example 9, the title compound (330 mg) was obtained aspale yellow amorphous powders.

¹H NMR(free base; 200 MHz, CDCl₃) δ 1.35–1.65 (4H, m), 1.75 (2H,quintet, J=7.4 Hz), 2.33 (3H, s), 2.44 (2H, t, J=7.5 Hz), 2.55–2.65 (2H,m), 2.71 (2H, t, J=7.5 Hz), 2.85–2.95 (4H, m), 3.02 (2H, t, J=7.8 Hz),3.22 (2H, t, J=8.4 Hz), 4.13 (2H, t, J=8.4 Hz), 7.05–7.40 (4H, m), 7.67(1H, s), 7.72 (1H, s). elementary analysis as C₂₆H₃₁ClN₂O₂.HCl.0.5H₂Ocalculation value: C, 64.46; H, 6.87; N, 5.78. experimental value: C,64.75; H, 6.70; N, 5.65.

Example 308-[6-[[2-(3-Chlorophenyl)ethyl](methyl)amino]hexanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using8-(6-bromohexanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(500 mg) obtained in Reference Example 2 andN-[2-(3-chlorophenyl)ethyl]-N-methylamine (288 mg) according to the samemethod as that of Example 9, the title compound (235 mg) was obtained aspale yellow amorphous powders.

¹H NMR(free base; 200 MHz, CDCl₃) δ 1.35–1.60 (4H, m), 1.74 (2H, tt,J=7.4, 7.4 Hz), 2.29 (3H, s), 2.40 (2H, t, J=7.5 Hz), 2.50–2.80 (6H, m),2.91 (2H, t, J=7.5 Hz), 3.02 (2H, t, J=7.8 Hz), 3.22 (2H, t, J=8.4 Hz),4.13 (2H, t, J=8.4 Hz), 7.00–7.40 (4H, m), 7.67 (1H, s), 7.71 (1H, s).

Example 318-[6-[[2-(3-Fluorophenyl)ethyl](methyl)amino]hexanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using8-(6-bromohexanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(500 mg) obtained in Reference Example 2 andN-[2-(3-fluorophenyl)ethyl]-N-methylamine (241 mg) according to the samemethod as that of Example 9, the title compound (120 mg) was obtained aspale yellow amorphous powders.

¹H NMR(free base; 300 MHz, CDCl₃) δ 1.35–1.65 (4H, m), 1.74 (2H,quintet, J=7.4 Hz), 2.29 (3H, s), 2.41 (2H, t, J=7.5 Hz), 2.55–2.65 (2H,m), 2.65–2.80 (4H, m), 2.91 (2H, t, J=7.5 Hz), 3.02 (2H, t, J=7.8 Hz),3.22 (2H, t, J=8.4 Hz), 4.12 (2H, t, J=8.4 Hz), 6.80–7.00 (3H, m),7.20–7.30 (1H, m), 7.67 (1H, s), 7.72 (1H, s).

Example 328-[6-[Ethyl-(2-phenylethyl)amino]hexanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using8-(6-bromohexanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(500 mg) obtained in Reference Example 2 andN-ethyl-N-(2-phenylethyl)amine (234 mg) according to the same method asthat of Example 9, the title compound (140 mg) was obtained as paleyellow amorphous powders.

¹H NMR(free base; 300 MHz, CDCl₃) δ 1.05 (3H, t, J=7.2 Hz), 1.30–1.65(4H, m), 1.75 (2H, tt, J=7.5, 7.5 Hz), 2.51 (2H, t, J=7.5 Hz), 2.61 (2H,q, J=7.2 Hz), 2.65–2.80 (6H, m), 2.91 (2H, t, J=7.2 Hz), 3.02 (2H, t,J=7.8 Hz), 3.23 (2H, t, J=8.4 Hz), 4.12 (2H, t, J=8.4 Hz), 7.15–7.30(5H, m), 7.67 (1H, s), 7.72 (1H, s).

Example 338-(6-[Ethyl-[2-(2-methoxyphenyl)ethyl]amino]hexanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using8-(6-bromohexanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(500 mg) obtained in Reference Example 2 andN-ethyl-N-[2-(2-methoxyphenyl)ethyl]amine (281 mg) according to the samemethod as that of Example 9, the title compound (190 mg) was obtained aspale yellow amorphous powders.

¹H NMR(free base; 200 MHz, CDCl₃) δ 1.07 (3H, t, J=7.2 Hz), 1.30–1.65(4H, m), 1.76 (2H, tt, J=7.4, 7.4 Hz), 2.40–2.80 (10H, m), 2.91 (2H, t,J=7.4 Hz), 3.02 (2H, t, J=7.8 Hz), 3.22 (2H, t, J=8.4 Hz), 3.81 (3H, s),4.13 (2H, t, J=8.4 Hz), 6.80–6.95 (2H, m), 7.10–7.20 (2H, m), 7.67 (1H,s), 7.72 (1H, s).

Example 348-(6-[Isopropyl-[2-(2-methoxyphenyl)ethyl]amino]hexanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using8-(6-bromohexanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(700 mg) obtained in Reference Example 2 andN-isopropyl-N-[2-(2-methoxyphenyl)ethyl]amine (425 mg) according to thesame method as that of Example 9, the title compound (400 mg) wasobtained as pale yellow amorphous powders.

¹H NMR(free base; 300 MHz, CDCl₃) δ 1.00 (6H, d, J=6.6 Hz), 1.30–1.60(4H, m), 1.75 (2H, tt, J=7.4, 7.4 Hz), 2.47 (2H, t, J=7.5 Hz), 2.55–2.75(6H, m), 2.85–3.05 (5H, m), 3.21 (2H, t, J=8.4 Hz), 3.81 (3H, s), 4.12(2H, t, J=8.4 Hz), 6.80–6.90 (2H, m), 7.10–7.20 (2H, m), 7.67 (1H, s),7.72 (1H, s).

Example 358-[6-[[2-(2-Chlorophenyl)ethyl](isopropyl)amino]hexanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using8-(6-bromohexanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(700 mg) obtained in Reference Example 2 andN-[2-(2-chlorophenyl)ethyl]-N-isopropylamine (435 mg) according to thesame method as that of Example 9, the title compound (350 mg) wasobtained as pale yellow amorphous powders.

¹H NMR(free base; 300 MHz, CDCl₃) δ 1.00 (6H, d, J=6.6 Hz), 1.30–1.55(4H, m), 1.73 (2H, tt, J=7.4, 7.4 Hz), 2.46 (2H, t, J=7.5 Hz), 2.55–2.65(2H, m), 2.71 (2H, t, J=7.8 Hz), 2.75–3.05 (7H, m), 3.21 (2H, t, J=8.4Hz), 4.12 (2H, t, J=8.4 Hz), 7.05–7.35 (4H, m), 7.67 (1H, s), 7.72 (1H,s).

Example 368-[5-[(3-Phenylpropyl)amino]pentanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using tert-butyl5-oxo-5-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)pentyl(3-phenylpropyl)carbamate(660 mg) obtained in Reference Example 34 according to the same methodas that of Example 1, the title compound (443 mg) was obtained ascolorless crystals having a melting point of 116 to 118° C.

¹H NMR(200 MHz, DMSO-d₆) δ 1.50–1.80 (4H, m), 1.94 (2H, tt, J=7.5, 7.5Hz), 2.50–2.70 (4H, m), 2.75–3.05 (8H, m), 3.17 (2H, t, J=8.4 Hz), 3.99(2H, t, J=8.4 Hz), 7.15–7.35 (5H, m), 7.73 (2H, s), 8.80–9.10 (2H, br).elementary analysis as C₂₅H₃₀N₂O₂.HCl.H₂O calculation value: C, 67.48;H, 7.47; N, 6.30. experimental value: C, 67.45; H, 7.71; N, 6.26.

Example 378-[6-[(3-Phenylpropyl)amino]hexanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using tert-butyl6-oxo-6-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)hexyl(3-phenylpropyl)carbamate(906 mg) obtained in Reference Example 35 according to the same methodas that of Example 1, the title compound (350 mg) was obtained ascolorless crystals having a melting point of 132 to 134° C.

¹H NMR(300 MHz, DMSO-d₆) δ 1.30–1.45 (2H, m), 1.50–1.75 (4H, m), 1.94(2H, tt, J=7.5, 7.5 Hz), 2.59 (2H, t, J=7.8 Hz), 2.65 (2H, t, J=7.8 Hz),2.75–3.00 (8H, m), 3.17 (2H, t, J=8.4 Hz), 3.98 (2H, t, J=8.4 Hz),7.15–7.35 (5H, m), 7.72 (2H, s), 8.80–9.10 (2H, br).

Example 388-(5-[[2-(2-Methoxyphenyl)ethyl]amino]pentanoyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using tert-butyl2-(2-methoxyphenyl)ethyl[5-oxo-5-(2-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)pentyl]carbamateobtained in Reference Example 36 according to the same method as that ofExample 1, the title compound (535 mg) was obtained as pale yellowcrystals having a melting point of 169 to 170° C.

¹H NMR(400 MHz, DMSO-d₆) δ 1.61–1.73 (4H, m), 1.88–1.97 (2H, m), 2.76(2H, t, J=6 Hz), 2.93–3.00 (8H, m), 3.57 (2H, s), 3.60 (2H, t, J=6 Hz),3.79 (3H, s), 6.89 (1H, t, J=7.5 Hz) 6.98 (1H, d, J=7.5 Hz), 7.17 (1H,d, J=7.4 Hz), 7.24 (1H, t, J=7.4 Hz), 7.71 (1H, s), 7.75 (1H, s), 9.12(2H, br s). IR (KBr) νcm⁻¹: 3418, 2951, 2771, 1708, 1670, 1604, 1498,1343, 1251, 1150. elementary analysis as C₂₅H₃₀N₂O₃.HCl calculationvalue: C, 67.78; H, 7.05; N, 6.32. experimental value: C, 67.45; H,7.01; N, 6.27.

Example 398-(5-[[2-(2-Chlorophenyl)ethyl]amino]pentanoyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-onehydrochloride

Using tert-butyl2-(2-chlorophenyl)ethyl[5-oxo-5-(2-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)pentyl]carbamateobtained in Reference Example 37 according to the same method as that ofExample 1, the title compound (585 mg) was obtained as pale yellowcrystals having a melting point of 179 to 180° C.

¹H NMR(400 MHz, DMSO-d₆) δ 1.66–1.72 (4H, m), 1.88–1.94 (2H, m), 2.76(2H, t, J=6 Hz), 2.96–3.01 (4H, m), 3.11–3.15 (4H, m), 3.57 (2H, s),3.60 (2H, t, J=6 Hz), 7.27–7.34 (2H, m), 7.38–7.41 (1H, m), 7.44–7.46(1H, m), 7.71 (1H, s), 7.75 (1H, s), 9.25 (2H, br s). IR (KBr)νcm⁻¹:3424, 2952, 2772, 1709, 1666, 1602, 1499, 1341, 1149. elementaryanalysis as C₂₄H₂₇ClN₂O₂.HCl calculation value: C, 64.43; H, 6.31; N,6.26. experimental value: C, 64.08; H, 6.36; N, 5.96.

Example 408-[5-[Methyl(2-phenylethyl)amino]pentanoyl]-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-onehydrochloride

Using8-(5-chloropentanoyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-oneobtained in Reference Example 3 and N-methyl-N-(2-phenylethyl)amineaccording to the same method as that of Example 9, the title compound(297 mg) was obtained as colorless amorphous powders.

¹H NMR(free base; 400 MHz, CDCl₃) δ 1.53–1.61 (2H, m), 1.71–1.78 (2H,m), 2.00–2.06 (2H, m), 2.30 (3H, s), 2.45 (2H, t, J=7.4 Hz), 2.58–2.62(2H, m), 2.75–2.83 (4H, m), 2.93 (2H, t, J=7.4 Hz), 3.54 (2H, s), 3.74(2H, t, J=6 Hz), 7.16–7.29 (5H, m), 7.73 (2H, s). IR (free base;KBr)νcm⁻¹: 1718, 1673, 1604, 1496, 1343, 1151.

Example 418-(5-[[2-(2-Methoxyphenyl)ethyl]amino]pentanoyl]-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-onehydrochloride

Using8-(5-chloropentanoyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-one(292 mg) obtained in Reference Example 3 andN-[2-(2-methoxyphenyl)ethyl]-N-methylamine (363 mg) according to thesame method as that of Example 9, the title compound (130 mg) wasobtained as W yellow amorphous powders.

¹H NMR(free base; 400 MHz, CDCl₃) δ 1.55–1.63 (2H, m), 1.72–1.79 (2H,m), 2.00–2.06 (2H, m), 2.32 (3H, s), 2.47 (2H, t, J=7.5 Hz), 2.56–2.60(2H, m), 2.77–2.83 (4H, m), 2.94 (2H, 5 t, J=7.5 Hz), 3.54 (2H, s), 3.74(2H, t, J=6 Hz), 3.81 (3H, s), 6.83–6.89 (2H, m), 7.12–7.19 (2H, m),7.74 (2H, s). IR (free base; KBr) νcm⁻¹: 1716, 1672, 1603, 1495, 1343,1243, 1152.

Example 428-[(5-[[2-(2-Chlorophenyl)ethyl](methyl)amino]pentanoyl]-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-onehydrochloride

Using8-(5-chloropentanoyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-oneobtained in Reference Example. 3 andN-[2-(2-chlorophenyl)ethyl]-N-methylamine according to-the same methodas that of Example 9, the title compound (85 mg) was obtained as paleyellow amorphous powders.

¹H NMR(free base; 400 MHz, CDC₃) δ 1.56–1.64 (2H, m), 1.71–1.79 (2H, m),2.00–2.07 (2H, m), 2.36 (3H, s), 2.50 (2H, t, J=7.5 Hz), 2.61–2.67 (2H,m), 2.82 (2H, t, J=6 Hz), 2.90–2.95 (4H, m), 3.55 (2H, s), 3.74 (2H, t,J=6 Hz), 7.11–7.25 (3H, m), 7.32 (1H, dd, J=5.5, 2 Hz) 7.74 (2H, s). IR(free base; KBr) νcm⁻¹: 1716, 1672, 1604, 1496, 1343, 1151.

Example 438-[(5-[[2-(3-Fluorophenyl)ethyl](methyl)amino]pentanoyl]-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-onehydrochloride

Using8-(5-chloropentanoyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-oneobtained in Reference Example 3 andN-[2-(3-fluorophenyl)ethyl]-N-methylamine according to the same methodas that of Example 9, the title compound (68 mg) was obtained as paleyellow amorphous powders.

¹H NMR(free base; 400 MHz, CDCl₃) δ 1.52–1.60 (2H, m), 1.72–1.78 (2H,m), 2.00–2.08 (2H, m), 2.29 (3H, s), 2.44 (2H, t, J=7.5 Hz), 2.58–2.62(2H, m), 2.74–2.78 (2H, m), 2.82 (2H, t, J=6 Hz), 2.93 (2H, t, J=7 Hz),3.55 (2H, s), 3.74 (2H, t, J=6 Hz), 6.85–6.93 (2H, m), 6.96 (1H, d,J=7.5 Hz), 7.20–7.25 (1H, m), 7.73 (2H, s). IR (free base; KBr) νcm⁻¹:1717, 1673, 1604, 1496, 1343, 1151.

Example 448-[5-[Ethyl(2-phenylethyl)amino]pentanoyl]-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-onehydrochloride

Using8-(5-chloropentanoyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-oneobtained in Reference Example 3 and N-ethyl-N-(2-phenylethyl)amineaccording to the same method as that of Example 9, the title compound(45 mg) was obtained as pale yellow amorphous powders.

¹H NMR(free base; 400 MHz, CDCl₃) δ 1.05 (3H, t, J=7 Hz), 1.54–1.59 (2H,m), 1.70–1.78 (2H, m), 2.00–2.06 (2H, m), 2.54 (2H, t, J=7 Hz), 2.61(2H, q, J=7 Hz), 2.68–2.75 (4H, m), 2.82 (2H, t, J=6 Hz), 2.92 (2H, t,J=6 Hz), 3.54 (2H, s), 3.74 (2H, t, J=6 Hz), 7.16–7.19 (3H, m) 7.25–7.30(2H, m), 7.73 (2H, s). IR (free base; KBr) νcm⁻¹: 1718, 1671, 1603,1496, 1342, 1150.

Example 458-(5-[Ethyl[2-(2-methoxyphenyl)ethyl]amino]pentanoyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-onehydrochloride

Using8-(5-chloropentanoyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-oneobtained in Reference Example 3 andN-ethyl-N-[2-(2-methoxyphenyl)ethyl]amine according to the same methodas that of Example 9, the title compound (44 mg) was obtained as paleyellow amorphous powders.

¹H NMR(free base; 400 MHz, CDCl₃) δ 1.07 (3H, t, J=7 Hz), 1.57–1.62 (2H,m), 1.71–1.79 (2H, m), 1.99–2.06 (2H, m), 2.57 (2H, t, J=7 Hz), 2.62(2H, q, J=7 Hz), 2.66–2.70 (2H, m), 2.73–2.78 (2H, m), 2.82 (2H, t, J=6Hz), 2.93 (2H, t, J=6 Hz), 3.54 (2H, s), 3.74 (2H, t, J=6 Hz), 3.81 (3H,s), 6.83–6.89 (3H, m), 7.11–7.19 (2H, m), 7.74 (2H, s). IR (free base;KBr) νcm⁻¹: 1717, 1672, 1602, 1494, 1342, 1243, 1150.

Example 468-[6-[(2-Phenylethyl)amino]hexanoyl]-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-onehydrochloride

Using8-(6-bromohexanoyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-one(350 mg) obtained in Reference Example 4 and 2-phenylethylamine (364 mg)according to the same method as that of Example 9, the title compound(73 mg) was obtained as pale yellow amorphous powders.

¹H NMR(free base; 400 MHz, CDCl₃) δ 1.35–1.42 (2H, m), 1.49–1.56 (2H,m), 1.60 (1H, br s), 1.69–1.77 (2H, m), 2.00–2.06 (2H, m), 2.63 (2H, t,J=7.4 Hz), 2.75–2.97 (8H, m), 3.54 (2H, s), 3.74 (2H, t, J=6 Hz),7.18–7.31 (5H, m), 7.72 (2H, s). IR (free base; KBr) νcm⁻¹: 1716, 1672,1604, 1496, 1343, 1150.

Example 478-(6-[[2-(2-Methoxyphenyl)ethyl]amino]hexanoyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-onehydrochloride

Using8-(6-bromohexanoyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-oneobtained in Reference Example 4 and 2-(2-methoxyphenyl)ethylamineaccording to the same method as that of Example 9, the title compound(190 mg) was obtained as pale yellow amorphous powders.

¹H NMR(free base; 400 MHz, CDCl₃) δ 1.36–1.43 (2H, m), 1.49–1.57 (3H,m), 1.70–1.77 (2H, m), 2.00–2.06 (2H, m), 2.64 (2H, t, J=7.4 Hz),2.80–2.83 (6H, m), 2.90 (2H, t, J=7.4 Hz), 3.54 (2H, s), 3.73 (2H, t,J=6 Hz), 3.81 (3H, s), 6.86 (1H, t, J=8.3 Hz), 6.89 (1H, d, J=7.3 Hz),7.13–7.21 (2H, m), 7.72 (2H, s). IR (free base; KBr) νcm-⁻¹: 1715, 1672,1603, 1495, 1343, 1242, 1150.

Example 488-(6-[[2-(2-Chlorophenyl)ethyl]amino]hexanoyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-onehydrochloride

Using8-(6-bromohexanoyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-oneobtained in Reference Example 4 and 2-(2-chlorophenyl)ethylamineaccording to the same method as that of Example 9, the title compound(30 mg) was obtained as pale yellow amorphous powders.

¹H NMR(free base; 400 MHz, CDCl₃) δ 1.37–1.45 (2H, m), 1.51–1.58 (2H,m), 1.56 (1H, br s), 1.71–1.78 (2H, m), 2.00–2.07 (2H, m), 2.66 (2H, t,J=7.5 Hz), 2.82 (2H, t, J=6 Hz), 2.85–2.98 (6H, m), 3.55 (2H, s), 3.74(2H, t, J=6 Hz), 7.13–7.25 (3H, m), 7.34 (1H, dd, J=7, 2 Hz), 7.73 (2H,s). IR (free base; KBr) νcm⁻¹: 1715, 1671, 1604, 1496, 1343, 1150.

Example 498-[6-[(2-Phenylethyl]amino]hexanoyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-onehydrochloride

Using8-(6-bromohexanoyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-oneobtained in Reference Example 4 and N-methyl-N-(2-phenylethyl)amineaccording to the same method as that of Example 9, the title compound(30 mg) was obtained as pale yellow amorphous powders.

¹H NMR(free base; 400 MHz, CDCl₃) δ 1.36–1.42 (2H, m), 1.50–1.58 (2H,m), 1.71–1.78 (2H, m), 2.00–2.06 (2H, m), 2.30 (3H, s), 2.41 (2H, t, J=7Hz), 2.58–2.62 (2H, m), 2.75–2.83 (4H, m), 2.91 (2H, t, J=7 Hz), 3.54(2H, s), 3.73 (2H, t, J=6 Hz), 7.16–7.29 (5H, m), 7.73 (2H, s). IR (freebase; KBr) νcm⁻¹: 1718, 1673, 1604, 1496, 1343, 1151.

Example 508-(6-[[2-(2-Methoxyphenyl)ethyl]amino]hexanoyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-onehydrochloride

Using8-(6-bromohexanoyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-oneobtained in Reference Example 4 andN-[2-(2-methoxyphenyl)ethyl]-N-methylamine according to the same methodas that of Example 9, the title compound (250 mg) was obtained as paleyellow amorphous powders.

¹H NMR(free base; 400 MHz, CDCl₃) δ 1.37–1.43 (2H, m), 1.51–1.59 (2H,m), 1.71–1.79 (2H, m), 2.00–2.06 (2H, m), 2.31 (3H, s), 2.42. (2H, t,J=7.5 Hz), 2.55–2.59 (2H, m), 2.76–2.83 (4H, m), 2.92 (2H, t, J=7.5 Hz),3.54 (2H, s), 3.73 (2H, t, J=6 Hz), 3.81 (3H, s), 6.83–6.89 (2H, m),7.12–7.19 (2H, m), 7.74 (2H, s). IR (free base; KBr) νcm⁻¹: 1715, 1672,1603, 1495, 1343, 1242, 1150.

Example 518-(6-[[2-(2-Chlorophenyl)ethyl]amino]hexanoyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-onehydrochloride

Using8-(6-bromohexanoyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-oneobtained in Reference Example 4 andN-[2-(2-chlorophenyl)ethyl]-N-methylamine according to the same methodas that of Example 9, the title compound (256 mg) was obtained as paleyellow amorphous powders.

¹H NMR(free base; 400 MHz, CDCl₃) δ 1.37–1.43 (2H, m), 1.51–1.58 (2H,m), 1.71–1.79 (2H, m), 2.00–2.06 (2H, m), 2.33 (3H, s), 2.44 (2H, t,J=7.5 Hz), 2.58–2.62 (2H, m), 2.82 (2H, t, J=6 Hz), 2.88–2.94 (4H, m),3.54 (2H, s), 3.74 (2H, t, J=6 Hz), 7.11–7.24 (3H, m), 7.32 (1H, dd,J=5.5, 2 Hz), 7.73 (2H, s) IR (free base;. KBr) νcm⁻¹: 1718, 1673, 1604,1496, 1343, 1151.

Example 528-(6-[[2-(3-Fluorophenyl)ethyl]amino]hexanoyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-onehydrochloride

Using8-(6-bromohexanoyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-oneobtained in Reference Example 4 andN-[2-(3-fluorophenyl)ethyl]-N-methylamine according to the same methodas that of Example 9, the title compound (190 mg) was obtained as paleyellow amorphous powders.

¹H NMR(free base; 400 MHz, CDCl₃) δ 1.36–1.42 (2H, m), 1.49–1.57 (2H,m), 1.71–1.78 (2H, m), 2.00–2.07 (2H, m), 2.29 (3H, s), 2.40 (2H, t,J=7.5 Hz), 2.57–2.61 (2H, m), 2.74–2.79 (2H, m), 2.84 (2H, t, J=6 Hz),3.54 (2H, s), 3.74 (2H, t, J=6 Hz), 6.85–6.91 (2H, m), 6.97 (1H, d,J=7.5 Hz), 7.20–7.25 (1H, m), 7.74 (2H, s). IR (free base; KBr) νcm⁻:1717, 1672, 1604, 1496, 1343, 1150.

Example 538-[6-[Ethyl(2-phenylethyl)amino]hexanoyl]-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-onehydrochloride

Using8-(6-bromohexanoyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-oneobtained in Reference Example 4 and N-ethyl-N-(2-phenylethyl]amineaccording to the same method as that of Example 9, the title compound(137 mg) was obtained as pale yellow amorphous powders.

¹H NMR(free base; 400 MHz, CDCl₃) δ 1.05 (3H, t, J=7 Hz), 1.36–1.42 (2H,m), 1.49–1.56 (2H, m), 1.71–1.79 (2H, m), 2.00–2.06 (2H, m), 2.50 (2H,t, J=7.5 Hz), 2.61 (2H, q, J=7 Hz), 2.67–2.76 (4H, m), 2.82 (2H, t, J=6Hz), 2.91 (2H, t, J=6 Hz), 3.54 (2H, s), 3.73 (2H, t, J=6 Hz), 7.16–7.19(3H, m), 7.25–7.29 (2H, m), 7.73 (2H, s). IR (free base; KBr) νcm⁻¹:1718, 1673, 1604, 1496, 1342, 1150.

Example 548-(6-[Ethyl[2-(2-methoxyphenyl)ethyl]amino]hexanoyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-onehydrochloride

Using8-(6-bromohexanoyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-oneobtained in Reference Example 4 and N-[2-(2-methoxyphenyl)ethyl]amineaccording to the same method as that of Example 9, the title compound(145 mg) was obtained as pale yellow amorphous powders.

¹H NMR(free base; 400 MHz, CDCl₃) δ 1.06 (3H, t, J=7 Hz), 1.37–1.43 (2H,m), 1.51–1.59 (2H, m), 1.72–1.80 (2H, m), 2.00–2.06 (2H, m), 2.52 (2H,t, J=7.5 Hz), 2.61 (2H, q, J=7 Hz), 2.66–2.69 (2H, m), 2.72–2.77 (2H,m), 2.82 (2H, t, J=6 Hz), 2.92 (2H, t, J=6 Hz), 3.54 (2H, s), 3.73 (2H,t, J=6 Hz), 3.81(3H, s), 6.83–6.89(2H, m), 7.11–7.19 (2H, m), 7.73 (2H,s). IR (free base; KBr) νcm⁻¹: 1718, 1673, 1603, 1495, 1342, 1242, 1150.

Example 558-(6-[Isopropyl[2-(2-methoxyphenyl)ethyl]amino]hexanoyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-onehydrochloride

Using8-(6-bromohexanoyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-oneobtained in Reference Example 4 andN-isopropyl-N-[2-(2-methoxyphenyl)ethyl]amine (425 mg) according to thesame method as that of Example 9, the title compound (45 mg) wasobtained as pale yellow amorphous powders.

¹H NMR(free base; 400 MHz, CDCl₃) δ 1.00 (6H, d, J=6.3 Hz), 1.36–1.42(2H, m), 1.48–1.55 (2H, m), 1.71–1.78 (2H, m), 1.99–2.05 (2H, m), 2.46(2H, t, J=7.3 Hz), 2.56–2.60 (2H, m), 2.69–2.73 (2H, m), 2.81 (2H, t,J=6 Hz), 2.91 (2H, t, J=7.3 Hz), 2.99 (1H, q, J=6.3 Hz), 3.53 (2H, s),3.72 (2H, t, J=6 Hz), 3.81 (3H, s), 6.82–6.88 (2H, m), 7.10–7.18 (2H,m), 7.73 (2H, s). IR (free base; neat) νcm⁻¹: 1713, 1674, 1603, 1495,1344, 1243, 1150.

Example 569-[5-[(2-Phenylethyl)amino]pentanolyl)-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-onehydrochloride

Using tert-butyl5-oxo-5-(3-oxo-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-9-yl)pentyl(2-phenylethyl)carbamate(315 mg) obtained in Reference Example 38 according to the same methodas that of Example 1, the title compound (264 mg) was obtained as yellowamorphous powders.

¹H NMR(400 MHz, CD₃OD) δ 1.71–1.85 (4H, m), 1.98–2.02 (2H, m), 2.69 (2H,t, J=7 Hz), 2.90 (2H, t, J=6 Hz), 3.00 (2H, t, J=7 Hz), 3.04–3.08 (2H,m), 3.10–3.14 (4H, m), 3.28–3.32 (2H, m), 3.90 (2H, t, J=6 Hz), 4.88(2H, s), 7.29–7.41 (5H, m), 7.74 (2H, d, J=4 Hz). IR (neat) νcm⁻¹: 3427,1670, 1604, 1484, 1366, 1298, 1165.

Example 579-(5-[[2-(2-Methoxyphenyl)ethyl]amino]pentanolyl)-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-onehydrochloride

Using tert-butyl2-(2-methoxyphenyl)ethyl[5-oxy-5-(3-oxo-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-9-yl)pentyl]carbamate(410 mg) obtained in Reference Example 39 according to the same methodas that of Example 1, the title compound (315 mg) was obtained as yellowamorphous powders.

¹H NMR(400 MHz, CD₃OD) δ 1.71–1.78 (4H, m), 1.85–1.91 (2H, m), 2.57 (2H,t, J=7 Hz), 2.79 (2H, t, J=7 Hz), 2.88 (2H, t, J=7 Hz), 2.96–3.03 (6H,m), 3.17 (2H, t, J=7 Hz), 3.77 (2H, t, J=7.5 Hz), 3.81 (3H, s), 4.79(2H, s), 6.87 (1H, t, J=7 Hz), 6.93 (1H, d, J=8 Hz), 7.17 (1H, d, J=7Hz), 7.22 (1H, t, J=7 Hz), 7.64 (2H, d, J=4 Hz). IR (neat) νcm⁻¹: 3431,1671, 1603, 1496, 1439, 1366, 1247, 1165.

Example 589-(5-[[2-(2-Chlorophenyl)ethyl]amino]pentanolyl)-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-onehydrochloride

Using tert-butyl2-(2-chlorophenyl)ethyl[5-oxy-5-(3-oxo-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-9-yl)pentyl]carbamate(380 mg) obtained in Reference Example 40 according to the same methodas that of Example 1, the title compound (235 mg) was obtained ascolorless powders having a melting point of 108 to 109° C.

¹H NMR(400 MHz, DMSO-d₆) δ 1.62–1.72 (4H, m), 1.81–1.87 (2H, m), 2.56(2H, t, J=6 Hz), 2.79 (2H, t, J=6 Hz), 2.90 (2H, t, J=7 Hz), 2.92–3.02(4H, m), 3.05–3.16 (4H, m), 3.75 (2H, t, J=6 Hz), 7.24–7.35 (2H, m),7.39 (1H, dd, J=7, 2 Hz), 7.45 (1H, dd, J=7, 2 Hz), 7.66 (2H, s), 9.18(2H, s). IR (KBr) νcm⁻¹: 3429, 2948, 1671, 1603, 1363, 1338, 1165.

Example 599-[5-[Methyl(2-phenylethyl]amino]pentanolyl)-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-onehydrochloride

Using9-(5-chloropentanoyl)-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-oneobtained in Reference Example 5 and N-methyl-N-(2-phenylethyl)amineaccording to the same method as that of Example 9, the title compound(310 mg) was obtained as pale yellow amorphous powders.

¹H NMR(free base; 400 MHz, CDCl₃) δ 1.53–1.61 (2H, m), 1.71–1.78 (2H,m), 1.93–1.99 (2H, m), 2.31 (3H, s), 2.45 (2H, t, J=7.4 Hz), 2.59–2.63(2H, m), 2.66–2.69 (2H, m), 2.75–2.79 (2H, m), 2.84 (2H, t, J=6 Hz),2.91–2.95 (4H, m), 3.89 (2H, t, J=6 Hz), 7.17–7.29 (5H, m), 7.61 (2H, d,J=5 Hz). IR (free base; KBr) νcm⁻¹: 1676, 1604, 1590, 1484, 1361, 1339,1161.

Example 609-[5-[[2-(2-Methoxyphenyl)ethyl](methyl)amino]pentanolyl)-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-onehydrochloride

Using9-(5-chloropentanoyl)-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-oneobtained in Reference Example 5 andN-[2-(2-methoxyphenyl)ethyl]-N-methylamine according to the same methodas that of Example 9, the title compound (165 mg) was obtained as paleyellow amorphous powders.

¹H NMR(free base; 400 MHz, CDCl₃) δ 1.55–1.62 (2H, m), 1.71–1.79 (2H,m), 1.93–1.99 (2H, m), 2.32 (3H, s), 2.46 (2H, t, J=7.4 Hz), 2.56–2.60(2H, m), 2.68 (2H, t, J=6 Hz), 2.77–2.80 (2H, m), 2.84 (2H, t, J=6 Hz),2.91–2.95 (4H, m), 3.81 (3H, s), 3.89 (2H, t, J=6 Hz), 6.83–6.89 (2H,m), 7.12–7.19 (2H, m), 7.62 (2H, d, J=5 Hz). IR (free base; KBr) νcm⁻¹:1674, 1603, 1494, 1361, 1339, 1243, 1160.

Example 61 9-[5-[[2-(2-Chlorophenyl)ethyl](methyl)aminopentanolyl)-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-onehydrochloride

Using9-(5-chloropentanoyl)-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-oneobtained in Reference Example 5 andN-[2-(2-chlorophenyl)ethyl]-N-methylamine according to the same methodas that of Example 9, the title compound (188 mg) was obtained as paleyellow amorphous powders.

¹H NMR(free base; 400 MHz, CDCl₃) δ 1.54–1.62 (2H, m), 1.71–1.78 (2H,m), 1.93–1.99 (2H, m), 2.32 (3H, s), 2.48 (2H, t, J=7 Hz), 2.59–2.63(2H, m), 2.67 (2H, t, J=6 Hz), 2.84 (2H, t, J=6 Hz), 2.88–2.96 (6H, m),3.89 (2H, t, J=6 Hz), 7.11–7.24 (3H, m), 7.32 (1H, d, d, J=5, 2 Hz),7.62 (2H, d, J=5 Hz). IR (free base; KBr) νcm⁻¹: 1673, 1604, 1483, 1438,1361, 1159.

Example 629-[5-[Ethyl(2-phenylethyl]amino)pentanolyl)-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-onehydrochloride

Using9-(5-chloropentanoyl)-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-oneobtained in Reference Example 5 and N-ethyl-N-(2-phenylethyl)amineaccording to the same method as that of Example 9, the title compound(45 mg) was obtained as pale yellow amorphous powders.

¹H NMR(free base; 400 MHz, CDCl₃) δ 1.05 (3H, t, J=7 Hz), 1.52–1.60 (2H,m), 1.70–1.77 (2H, m), 1.95–1.99 (2H, m), 2.55 (2H, t, J=7 Hz), 2.61(2H, q, J=7 Hz), 2.65–2.77 (6H, m), 2.84 (2H, t, J=6 Hz), 2.89–2.97 (4H,m), 3.89 (2H, t, J=6 Hz), 7.16–7.19 (3H, m), 7.25–7.30 (2H, m), 7.62(2H, d, J=5 Hz). IR (free base; KBr) νcm⁻¹: 1675, 1604, 1484, 1361,1299, 1160.

Example 639-(5-[Ethyl(2-(2-methoxyphenyl)ethyl]amino]pentanolyl)-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-onehydrochloride

Using9-(5-chloropentanoyl)-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-oneobtained in Reference Example 5 andN-ethyl-N-[2-(2-methoxyphenyl)ethyl]amine according to the same methodas that of Example 9, the title compound (70 mg) was obtained as paleyellow amorphous powders.

¹H NMR(free base; 400 MHz, CDCl₃) δ 1.07 (3H, t, J=7 Hz), 1.55–1.62 (2H,m), 1.71–1.78 (2H, m), 1.93–1.99 (2H, m), 2.56 (2H, t, J=7.5 Hz), 2.62(2H, q, J=7 Hz), 2.66–2.69 (4H, m), 2.73–2.78 (2H, m), 2.84 (2H, t, J=6Hz), 2.93 (4H, t, J=6 Hz), 3.81 (3H, s), 3.89 (2H, t, J=6 Hz), 6.83–6.89(2H, m), 7.11–7.19 (2H, m), 7.62 (2H, d, J=5 Hz). IR (free base; KBr)νcm⁻¹: 1674, 1603, 1494, 1361, 1339, 1243, 1160.

Example 649-[6-[(2-Phenylethyl)amino]hexanoyl]-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-onehydrochloride

Using9-(6-bromohexanoyl)-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-oneobtained in Reference Example 6 and 2-phenylethylamine according to thesame method as that of Example 9, the title compound (123 mg) wasobtained as pale yellow amorphous powders.

¹H NMR(free base; 400 MHz, CDCl₃) δ 1.35–1.42 (2H, m), 1.49–1.56 (3H,m), 1.69–1.77 (2H, m), 1.93–1.99 (2H, m), 2.61–2.69 (4H, m), 2.78–2.95(10H, m), 3.89 (2H, t, J=6 Hz), 7.18–7.31 (5H, m), 7.61 (2H, d, J=5Hz).IR (free base; KBr) νcm⁻¹: 1675, 1604, 1484, 1437, 1362, 1339, 1161.

Example 659-(6-[[2-(2-Methoxyphenyl)ethyl]amino]hexanoyl]-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-onehydrochloride

Using9-(6-bromohexanoyl)-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-oneobtained in Reference Example 6 and 2-(2-methoxyphenyl)ethylamineaccording to the same method as that of Example 9, the title compound(190 mg) was obtained as pale yellow amorphous powders.

¹H NMR(free base; 400 MHz, CDCl₃) δ 1.36–1.44 (2H, m), 1.50–1.57 (3H,m), 1.70–1.77 (2H, m), 1.92–1.99 (2H, m), 2.62–2.69 (4H, m), 2.82–2.85(6H, m), 2.89–2.96 (4H, m), 3.81 (3H, s), 3.89 (2H, t, J=6 Hz), 6.85(1H, d, J=8.3 Hz), 6.89 (1H, d, J=7.4 Hz), 7.14–7.20 (2H, m), 7.61 (2H,d, J=5 Hz). IR (free base; KBr) νcm⁻¹: 1673, 1603, 1494, 1362, 1339,1243, 1160.

Example 669-(6-[[2-(2-Chlorophenyl)ethyl]amino]hexanoyl)-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-onehydrochloride

Using9-(6-bromohexanoyl)-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-oneobtained in Reference Example 6 and 2-(2-chlorophenyl)ethylamineaccording to the same method as that of Example 9, the title compound(148 mg) was obtained as pale yellow amorphous powders.

¹H NMR(free base; 400 MHz, CDCl₃) δ 1.37–1.43 (2H, m), 1.51–1.58 (3H,m), 1.71–1.78 (2H, m), 1.95–2.00 (2H, m), 2.65–2.70 (4H, m), 2.84 (2H,t, J=7.5 Hz), 2.86–2.96 (8H, m), 3.89 (2H, t, J=6 Hz), 7.13–7.25 (3H,m), 7.34 (1H, dd, J=7, 2 Hz), 7.61 (2H, d, J=5 Hz). IR (free base; KBr)νcm⁻¹: 1673, 1603, 1483, 1361, 1159.

Example 679-(6-[(2-Phenylethyl]amino]hexanoyl]-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-onehydrochloride

Using9-(6-bromohexanoyl)-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-oneobtained in Reference Example 6 and N-methyl-N-(2-phenylethyl)amineaccording to the same method as that of Example 9, the title compound(225 mg) was obtained as pale yellow amorphous powders.

¹H NMR(free base; 400 MHz, CDCl₃) δ 1.37–1.43 (2H, m), 1.51–1.58 (2H,m), 1.71–1.78 (2H, m), 19.3–1.99 (2H, m), 2.30 (3H, s), 2.41 (2H, t, J=7Hz), 2.58–2.62 (2H, m), 2.67 (2H, t, J=6 Hz), 2.75–2.79 (2H, m), 2.84(2H, t, J=6 Hz), 2.89–2.95 (4H, m), 3.89 (2H, t, J=6 Hz), 7.18–7.29 (5H,m), 7.61 (2H, d, J=5 Hz). IR (free base; KBr) νcm⁻¹: 1676, 1604, 1590,1484, 1361, 1338, 1161.

Example 689-(6-[[2-(2-Methoxyphenyl)ethyl]amino]hexanoyl)-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-onehydrochloride

Using9-(6-bromohexanoyl)-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-oneobtained in Reference Example 6 andN-[2-(2-methoxyphenyl)ethyl]-N-methylamine according to the same methodas that of Example 9, the title compound (255 mg) was obtained as paleyellow amorphous powders.

¹H NMR(free base; 400 MHz, CDCl₃) δ 1.36–1.43 (2H, m), 1.51–1.58 (2H,m), 1.71–1.79 (2H, m), 1.93–1.99 (2H, m), 2.32 (3H, s), 2.42 (2H, t, J=7Hz), 2.55–2.59 (2H, m), 2.67 (2H, t, J=6 Hz), 2.76–2.80 (2H, m), 2.83(2H, t, J=6 Hz), 2.90–2.95 (4H, m), 3.81 (3H, s), 3.89 (2H, t, J=6 Hz),6.83–6.89 (2H, m), 7.12–7.19 (2H, m), 7.61 (2H, d, J=5 Hz). IR (freebase; KBr) νcm⁻¹: 1676, 1603, 1589, 1494, 1361, 1243, 1161.

Example 699-[6-[[2-(2-Chlorophenyl)ethyl](methyl)amino]hexanoyl]-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-onehydrochloride

Using9-(6-bromohexanoyl)-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-oneobtained in Reference Example 6 andN-[2-(2-chlorophenyl)ethyl]-N-methylamine according to the same methodas that of Example 9, the title compound (372 mg) was obtained as paleyellow amorphous powders.

¹H NMR(free base; 400 MHz, CDCl₃) δ 1.35–1.43 (2H, m), 1.51–1.59 (2H,m), 1.71–1.78 (2H, m), 1.93–1.99 (2H, m), 2.33 (3H, s), 2.44 (2H, t,J=7.5 Hz), 2.58–2.62 (2H, m), 2.68 (2H, t, J=6 Hz), 2.84 (2H, t, J=6Hz), 2.88–2.99 (6H, m), 3.89 (2H, t, J=6 Hz), 7.11–7.24 (3H, m), 7.32(1H, d, d, J=5, 2 Hz), 7.62 (2H, d, J=5 Hz). IR (free base; KBr) νcm⁻¹:1674, 1604, 1438, 1360, 1299, 1159.

Example 709-[6-[[2-(3-Flurophenyl)ethyl](methyl)amino]hexanoyl]-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-onehydrochloride

Using9-(6-bromohexanoyl)-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-oneobtained in Reference Example 6 andN-[2-(3-fluorophenyl)ethyl]-N-methylamine according to the same methodas that of Example 9, the title compound (303 mg) was obtained as paleyellow amorphous powders.

¹H NMR(free base; 400 MHz, CDCl₃) δ 1.36–1.42 (2H, m), 1.49–1.55 (2H,m), 1.70–1.78 (2H, m), 1.93–1.99 (2H, m), 2.29 (3H, s), 2.40 (2H, t,J=7.5 Hz), 2.58–2.62 (2H, m), 2.68 (2H, t, J=6 Hz), 2.74–2.78 (2H, m),2.85 (2H, t, J=6 Hz), 2.89–2.96 (4H, m), 3.89 (2H, t, J=6 Hz), 6.86–6.92(2H, m), 6.97 (1H, d, J=7.5 Hz), 7.20–7.25 (1H, m), 7.62 (2H, d, J=5Hz). IR (free base; KBr) νcm⁻¹: 1676, 1604, 1589, 1486, 1361, 1339,1161.

Example 719-[6-[Ethyl(2-phenylethyl)amino]hexanoyl]-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-onehydrochloride

Using9-(6-bromohexanoyl)-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-oneobtained in Reference Example 6 and N-ethyl-N-(2-phenylethyl)amineaccording to the same method as that of Example 9, the title compound(285 mg) was obtained as pale yellow amorphous powders.

¹H NMR(free base; 400 MHz, CDCl₃) δ 1.05 (3H, t, J=7 Hz), 1.34–1.42 (2H,m), 1.49–1.56 (2H, m), 1.71–1.78 (2H, m), 1.93–1.99 (2H, m), 2.50 (2H,t, J=7.5 Hz), 2.61 (2H, q, J=7 Hz), 2.66–2.77 (6H, m), 2.84 (2H,t,J=6Hz), 2.89–2.95 (4H, m), 3.89 (2H, t, J=6 Hz), 7.16–7.20 (3H, m),7.25–7.29 (2H, m), 7.62 (2H, d, J=5 Hz). IR (free base; KBr) νcm⁻¹:1676, 1603, 1589, 1494, 1361, 1243, 1161.

Example 729-(6-[Ethyl[2-(2-methoxyphenyl)ethyl]amino]hexanoyl)-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-onehydrochloride

Using9-(6-bromohexanoyl)-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-oneobtained in Reference Example 6 andN-ethyl-N-[2-(2-methoxyphenyl)ethyl]amine according to the same methodas that of Example 9, the title compound (395 mg) was obtained as paleyellow amorphous powders.

¹H NMR(free base; 400 MHz, CDCl₃) δ 1.07 (3H, t, J=7 Hz), 1.37–1.43 (2H,m), 1.51–1.59 (2H, m), 1.72–1.79 (2H, m), 1.93–1.99 (2H, m), 2.52 (2H,t, J=7.5 Hz), 2.62 (2H, q, J=7 Hz), 2.66–2.69 (4H, m), 2.72–2.82 (2H,m), 2.85 (2H, t, J=6 Hz), 2.92 (4H, t, J=6 Hz), 3.81 (3H, s), 3.89 (2H,t, J=6 Hz), 6.83–6.89 (2H, m), 7.11–7.19 (2H, m), 7.62 (2H, d, J=5 Hz).IR (free base; KBr) νcm⁻¹: 1675, 1603, 1493, 1361, 1242, 1159.

Example 739-(6-[Isopropyl[2-(2-methoxyphenyl)ethyl]amino]hexanoyl)-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-onehydrochloride

Using9-(6-bromohexanoyl)-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-oneobtained in Reference Example 6 andN-isopropyl-N-[2-(2-methoxyphenyl)ethyl]amine according to the samemethod as that of Example 9, the title compound (147 mg) was obtained aspale yellow amorphous powders.

¹H NMR(free base; 400 MHz, CDCl₃) δ 1.00 (6H, d, J=6.3 Hz), 1.36–1.42(2H, m), 1.48–1.54 (2H, m), 1.71–1.78 (2H, m), 1.93–1.99 (2H, m), 2.47(2H, t, J=7.3 Hz), 2.57–2.60 (2H, m), 2.65–2.74 (4H, m), 2.82–2.85 (2H,m), 2.89–2.95 (4H, m), 2.98 (1H, q, J=6.3 Hz), 3.81 (3H, s), 3.89 (2H,t, J=6 Hz), 6.82–6.88 (2H, m), 7.11–7.19 (2H, m), 7.62 (2H, d, J=5 Hz).IR (free base; neat) νcm⁻¹: 1676, 1604, 1494, 1360, 1243, 1162.

Example 741-(1-Acetyl-2,3-dihydro-1H-indol-5-yl)-5-[[2-(2-methoxyophenyl)ethyl]amino]-1-pentanonehydrochloride

Using tert-butyl5-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-5-oxopentyl[2-(2-methoxyphenyl)ethyl]carbamate(170 mg) obtained in Reference Example 7 according to the same method asthat of Example 1, the title compound (87 mg) was obtained as colorlesscrystals having a melting point of 175 to 176° C.

¹H NMR(400 MHz, DMSO-d₆) δ 1.58–1.72 (4H, m), 2.18 (3H, s), 2.90–3.05(8H, m), 3.17 (2H, t, J=8.5 Hz), 3.79 (3H, s), 4.14 (2H, t, J=8.5 Hz),6.90 (1H, t, J=7.5 Hz), 6.99 (1H, d, J=7.5 Hz), 7.16 (1H, d, J=7.5 Hz),7.24 (1H, t, J=8.3 Hz), 7.82–7.85 (2H, m), 8.08 (1H, d, J=8.3 Hz), 8.91(2H, br s). IR (KBr) νcm⁻¹: 2955, 2789, 1680, 1661, 1603, 1496, 1441,1440, 1255.

Example 756-(5-[[2-(2-Methoxyphenyl)ethyl]amino]pentanoyl)-2H-1,4-benzoxazin-3(4H)-onehydrochloride

Using 6-(5-chloropentanoyl)-2H-1,4-benzoxazin-3(4H)-one obtained inReference Example 7 and 2-(2-methoxyphenyl)ethylamine according to thesame method as that of Example 1, the title compound was obtained ascolorless amorphous powders.

¹H NMR(300 MHz, DMSO-d₆) δ 1.66 (4H, s), 2.93–3.02 (8H, m), 3.80 (3H,s), 4.69 (2H, s), 6.89–6.94 (1H, m), 6.99–7.07 (2H, m), 7.18 (1H, d,J=6.3 Hz), 7.23–7.28 (1H, m), 7.52 (1H, d, J=2.1 Hz), 7.63 (1H, dd,J=8.6, 2.1 Hz), 8.98 (2H, br s), 10.94 (1H, s). MS m/z: 383 [M+H]⁺

Example 768-[5-(1,3,4,5-Tetrahydro-2H-2-benzazepin-2-yl)pentanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one

Using8-(5-chloropentanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(600 mg) obtained in Reference Example 1 and2,3,4,5-tetrahydro-1H-2-benzazepine (332 mg) according to the samemethod as that of Example 9, the title compound (407 mg) was obtained ascolorless amorphous powders.

¹H NMR(free base; 200 MHz, CDCl₃) δ 1.45–1.80 (6H, m), 2.39 (2H, t,J=7.4 Hz), 2.71 (2H, t, J=7.6 Hz), 2.80–3.30 (10H, m), 3.88 (2H, s),4.12 (2H, t, J=8.4 Hz), 7.00–7.20 (4H, m), 7.65 (1H, s), 7.69 (1H, s).

Example 778-[5-(7-Methoxy-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)pentanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using8-(5-chloropentanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(500 mg) obtained in Reference Example 1 and7-methoxy-2,3,4,5-tetrahydro-1H-2-benzazepine (304 mg) according to thesame method as that of Example 9, the title compound (294 mg) wasobtained as colorless crystals having a melting point of 167 to 168° C.

¹H NMR(free base; 200 MHz, CDCl₃) δ 1.45–1.80 (6H, m), 2.38 (2H, t,J=7.4 Hz), 2.71 (2H, t, J=7.6 Hz), 2.80–3.15 (8H, m), 3.21 (2H, t, J=8.4Hz), 3.78 (3H, s), 3.84 (2H, s), 4.13 (2H, t, J=8.4 Hz), 6.61 (1H, dd,J=8.0, 2.6 Hz), 6.69 (1H, d, J=2.6 Hz), 7.02 (1H, d, J=8.4 Hz), 7.66(1H, s), 7.70 (1H, s).

Example 788-[6-(1,3,4,5-Tetrahydro-2H-2-benzazepin-2-yl)pentanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using8-(6-bromohexanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(500 mg) obtained in Reference Example 2 and2,3,4,5-tetrahydro-1H-2-benzazepine (252 mg) according to the samemethod as that of Example 9, the title compound (463 mg) was obtained ascolorless crystals having a melting point of 195 to 197° C.

¹H NMR(free base; 200 MHz, CDCl₃) δ 1.25–1.85 (8H, m), 2.35 (2H, t,J=7.4 Hz), 2.71 (2H, t, J=7.6 Hz), 2.80–3.00 (4H, m), 3.02 (2H, t, J=7.6Hz), 3.11 (2H, t, J=5.4 Hz), 3.22 (2H, t, J=8.4 Hz), 3.88 (2H, s), 4.13(2H, t, J=8.4 Hz), 7.00–7.20 (4H, m), 7.66 (1H, s), 7.70 (1H, s).elementary analysis as C₂₇H₃₂N₂O₂.HCl calculation value: C, 70.58; H,7.34; N, 6.18. experimental value: C, 70.16; H, 7.32; N, 6.08.

Example 798-[6-(7-Methoxy-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)pentanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using8-(6-bromohexanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(500 mg) obtained in Reference Example 2 and7-methoxy-2,3,4,5-tetrahydro-1H-2-benzazepine (253 mg) according to thesame method as that of Example 9, the title compound (366 mg) wasobtained as pale yellow amorphous powders.

¹H NMR(free base; 200 MHz, CDCl₃) δ 1.24–1.80 (8H, m), 2.34 (2H, t,J=7.4 Hz), 2.71 (2H, t, J=7.6 Hz), 2.80–3.15 (8H, m), 3.22 (2H, t, J=8.4Hz), 3.78 (3H, s), 3.84 (2H, s), 4.13 (2H, t, J=8.4 Hz), 6.61 (1H, dd,J=8.0, 2.6 Hz), 6.69 (1H, d, J=2.6 Hz), 7.02 (1H, d, J=8.4 Hz), 7.66(1H, s), 7.70 (1H, s).

Example 808-[5-(1,3-Dihydro-2H-isoindol-2-yl)pentanolyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using8-(5-chloropentanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(600 mg) obtained in Reference Example 1 and isoindiline (269 mg)according to the same method as that of Example 9, the title compound(191 mg) was obtained as colorless crystals having a melting point of219 to 221° C.

¹H NMR(free base; 200 MHz, CDCl₃) δ 1.60–1.95 (4H, m), 2.60–2.80 (4H,m), 2.90–3.05 (4H, m), 3.19 (2H, t, J=8.4 Hz), 3.92 (4H, s), 4.12 (2H,t, J=8.4 Hz), 7.10 (4H, s), 7.69 (1H, s), 7.73 (1H, s).

Example 818-[3-[1-(2-Phenylethyl)-4-piperidinyl]propanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

(2-Bromoethyl)benzene (0.22 ml) was added dropwise to a suspension of8-[3-(4-piperidinyl)propanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(500 mg) and potassium carbonate (500 mg) in acetonitrile (10 ml) atroom temperature. After stirring at room temperature for 12 hours, thereaction mixture was concentrated under is reduced pressure. Water (15ml) and ethyl acetate (20 ml) were added to the residue, and extractedwith ethyl acetate. The extract was washed with brine, dried overanhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure. The resulting residue was purified by silica gelchromatography (eluting solvent; ethyl acetate-methanol. (9:1)) to givea free base compound of the title compound as a pale yellow oil (617mg).

¹H NMR(200 MHz, CDCl₃) δ 1.20–1.50(3H, m), 1.60–1.85(4H, m),1.90–2.10(2H, m), 2.50–3.10(12H, m), 3.21(2H, t, J=8.4 Hz), 4.12(2H, t,J=8.4 Hz), 7.10–7.35(5H, m), 7.68(1H, s), 7.72(1H, s).

A solution of the above free base compound (610 mg) in ethanol wastreated with 1 equivalent or more of hydrogen chloride (ethyl acetatesolution) to give the title compound as colorless crystals having amelting point of 219 to 221° C.

elementary analysis as C₂₇H₃₂N₂O₂.HCl calculation value: C, 71.58; H,7.34; N, 6.18. experimental value: C, 71.27; H, 7.13; N, 6.20.

Example 828-(3-[1-[2-(2-Methylphenyl)ethyl]-4-piperidinyl]propanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using8-[3-(4-piperidinyl)propanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(600 mg) and 1-(2-bromoethyl)-2-methylbenzene (432 mg) according to thesame method as that of Example 81, the title compound (624 mg), wasobtained as colorless crystals having a melting point of 215 to 216° C.

¹H NMR(free base; 200 MHz, CDCl₃) δ 1.25–1.50 (3H, m), 1.55–1.85 (4H,m), 1.90–2.20 (2H, m), 2.33 (3H, s), 2.45–2.60 (2H, m), 2.65–3.10 (10H,m), 3.23 (2H, t, J=8.4 Hz), 4.14 (2H, t, J=8.4 Hz), 7.13 (4H, s), 7.68(1H, s), 7.72 (1H, s). elementary analysis as C₂₈H₃₄N₂O₂.HCl.0.5H₂Ocalculation value: C, 70.64; H, 7.62; N, 5.88. experimental value: C,70.24; H, 7.66; N, 5.81.

Example 838-(3-[1-[2-(2-Fluorophenyl)ethyl]-4-piperidinyl]propanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using8-[3-(4-piperidinyl)propanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(600 mg) and 1-(2-bromoethyl)-2-fluorobenzene (367 mg) according to thesame method as that of Example 81, the title compound (380 mg) wasobtained as colorless crystals having a melting point of 210 to 212° C.

¹H NMR(free base; 200 MHz, CDCl₃) δ 1.20–1.45 (3H, m), 1.55–2.10 (6H,m), 2.50–3.10 (12H, m), 3.23 (2H, t, J=8.4 Hz), 4.14 (2H, t, J=8.4 Hz),6.95–7.30 (4H, m), 7.68 (1H, s), 7.72 (1H, s). elementary analysis asC₂₇H₃₁FN₂O₂.HCl.0.5H₂O calculation value: C, 67.56; H, 6.93; N, 5.84.experimental value: C, 67.92; H, 6.68; N, 5.79.

Example 848-(3-[1-[2-(3-Fluorophenyl)ethyl]-4-piperidinyl]propanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using8-[3-(4-piperidinyl)propanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(500 mg) and 1-(2-bromoethyl)-3-fluorobenzene (367 mg) according to thesame method as that of Example 81, the title compound (351 mg) wasobtained as colorless crystals having a melting point of 225 to 227° C.

¹H NMR(free base; 200 MHz, CDCl₃) δ 1.20–1.50 (3H, m), 1.60–1.85 (4H,m), 1.90–2.10 (2H, m), 2.50–3.10 (12H, m), 3.23 (2H, t, J=8.4 Hz), 4.14(2H, t, J=8.4 Hz), 6.80–7.00 (3H, m), 7.15–7.30 (1H, m), 7.68 (1H, s),7.72 (1H, s).

Example 858-(3-[1-[2-(3-Chlorophenyl)ethyl]-4-piperidinyl]propanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using8-[3-(4-piperidinyl)propanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(500 mg) and 1-(2-bromoethyl)-3-chlorobenzene (394 mg) according to thesame method as that of Example 81, the title compound (369 mg) wasobtained as colorless crystals having a melting point of 223 to 225° C.

¹H NMR(free base; 200 MHz, CDCl₃) δ 1.20–1.50 (3H, m), 1.60–1.85 (4H,m), 1.90–2.10 (2H, m), 2.45–3.10 (12H, m), 3.23 (2H, t, J=8.4 Hz), 4.14(2H, t, J=8.4 Hz), 7.00–7.30 (4H, m), 7.68 (1H, s), 7.73 (1H, s).elementary analysis as C₂₇H₃₁ClN₂O₂.HCl.H₂O calculation value: C, 64.16;H, 6.78; N, 5.54. experimental value: C, 63.92; H, 6.75; N, 5.52.

Example 868-[3-[1-(2,3-Dihydro-1H-inden-2-yl)-4-piperidinyl]propanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using8-[3-(4-piperidinyl)propanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(600 mg) and 2,3-dihydro-1H-inden-2-yl methanesulfonate (428 mg)according to the same method as that of Example 81, the title compound(326 mg) was obtained as colorless crystals having a melting point of290° C. (dec).

¹H NMR(free base; 200 MHz, CDCl₃) δ 1.10–1.40 (3H, m), 1.45–1.80 (4H,m), 1.85–2.00 (2H, m), 2.61 (2H, t, J=7.6 Hz), 2.70–3.20 (13H, m), 4.03(2H, t, J=8.4 Hz), 7.00–7.15 (4H, m), 7.57 (1H, s), 7.62 (1H, s).elementary analysis as C₂₈H₃₂N₂O₂.HCl.0.5H₂O calculation value: C,70.94; H, 7.23; N, 5.91. experimental value: C, 71.19; H, 6.97; N, 5.71.

Example 878-[3-[1-(3-Phenylpropyl)-4-piperidinyl]propanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride.

Using8-[3-(4-piperidinyl)propanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(500 mg) and (3-bromopropyl)benzene (0.245 ml) according to the samemethod as that of Example 81, the title compound (488 mg) was obtainedas colorless crystals having a melting point of 173 to 175° C.

¹H NMR(free base; 200 MHz, CDCl₃) δ 1.20–1.45 (3H, m), 1.60–2.00 (8H,m), 2.35 (2H, t, J=7.6 Hz), 2.61 (2H, t, J=8.0 Hz), 2.70 (2H, t, J=8.4Hz), 2.80–2.95 (4H, m), 3.01 (2H, t, J=8.0 Hz), 3.21 (2H, t, J=8.4 Hz),4.12 (2H, t, J=8.4 Hz), 7.05–7.35 (5H, m), 7.67 (1H, s), 7.71 (1H, s).elementary analysis as C₂₈H₃₄N₂O₂.HCl calculation value: C, 72.01; H,7.55; N, 6.00. experimental value: C, 71.68; H, 7.50; N, 5.73.

Example 888-[3-[1-(2-Phenoxyethyl)-4-piperidinyl]propanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using8-[3-(4-piperidinyl)propanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(500 mg) and (2-bromoethoxy)benzene (0.222 ml) according to the samemethod as that of Example 81, the title compound (190 mg) was obtainedas colorless amorphous powders.

¹H NMR(free base; 200 MHz, CDCl₃) δ 1.20–1.45 (3H, m), 1.60–1.85 (4H,m), 2.00–2.25 (2H, m), 2.71 (2H, t, J=7.6 Hz), 2.80 (2H, t, J=6.2 Hz),2.85–3.10 (6H, m), 3.22 (2H, t, J=8.4 Hz), 4.00–4.20 (4H, m), 6.85–7.00(3H, m), 7.20–7.35 (2H, m), 7.67 (1H, s), 7.71 (1H, s). elementaryanalysis as C₂₇H₃₂N₂O₃.HCl.0.5H₂O calculation value: C, 67.84; H, 7.17;N, 5.86. experimental value: C, 68.10; H, 7.22; N, 5.83.

Example 898-(3-[1-[2-(2-Ethoxyphenoxy)ethyl]-4-piperidinyl]propanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using8-[3-(4-piperidinyl)propanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(500 mg) and 1-(2-bromoethoxy)-2-ethoxybenzene (412 mg) according to thesame method as that of Example 81, the title compound (583 mg) wasobtained as colorless amorphous powders.

¹H NMR(free base; 200 MHz, CDCl₃) δ 1.20–1.50 (6H, m), 1.60–1.80 (4H,m), 2.00–2.25 (2H, m), 2.71 (2H, t, J=7.6 Hz), 2.80–3.15 (8H, m), 3.22(2H, t, J=8.4 Hz), 4.00–4.20 (6H, m), 6.85–6.95 (4H, m), 7.67 (1H, s),7.72 (1H, s). elementary analysis as C₂₉H₃₆N₂O₄.HCl.0.5H₂O calculationvalue: C, 66.72; H, 7.34; N, 5.37. experimental value: C, 66.75; H,7.26; N, 5.28.

Example 905-[5-[[2-(2-Chlorophenyl)ethyl](methyl)amino]pentanoyl]-1,3-dihydro-2H-benzimidazol-2-onehydrochloride

Using 5-(5-chloropentanoyl)-1,3-dihydro-2H-benzimidazol-2-one obtainedin Reference Example 9 and N-[2-(2-chlorophenyl)ethyl]-N-methylamineaccording to the same method as that of Example 9, the title compoundwas obtained as colorless crystals having a melting point of 234 to 235°C.

¹H NMR(300 MHz, DMSO-d₆) δ 1.68–1.79 (4H, m), 2.83 (3H, d, J=4.8 Hz),3.04–3.30 (8H, m), 7.03 (1H, d, J=8.4 Hz), 7.31–7.50 (5H, m), 7.69 (1H,dd, J=8.3, 1.7 Hz), 10.46 (1H, br s), 10.96 (1H, s), 11.10 (1H, s). MSm/z: 386 [M+H]⁺ elementary analysis as C₂₁H₂₄ClN₃O₂.HCl.0.5H₂Ocalculation value: C, 58.47; H, 6.08; N, 9.74. experimental value: C,58.49; H, 6.05; N, 9.51. MS, m/z: 386 [M+H]⁺

Example 915-[5-[[2-(2-Chlorophenyl)ethyl](methyl)amino]pentanoyl]-1,3-dimethyl-1,3-dihydro-2H-benzimidazol-2-onehydrochloride

Using5-(5-chloropentanoyl)-1,3-dimethyl-1,3-dihydro-2H-benzimidazol-2-oneobtained in Reference Example 10 andN-[2-(2-chlorophenyl)ethyl]-N-methylamine according to the same methodas that of Example 9, the title compound was obtained as colorlesscrystals having a melting point of 142 to 143° C.

¹H NMR(Free base; 200 MHz, CDCl₃) δ 1.64–1.83 (4H, m), 2.42 (3H, s),2.54–2.74 (4H, m), 2.93–3.02 (4H, m), 3.46 (3H, s), 3.47 (3H, s), 6.99(1H, d, J=8.4 Hz), 7.13–7.35 (4H, m), 7.63 (1H, d, J=1.2 Hz), 7.79 (1H,dd, J=8.2, 1.6 Hz). MS m/z: 414 [M+H]⁺

Example 921-(1-Acetyl-2,3-dihydro-1H-indol-5-yl)-5-[(2-phenylethyl)amino]-1-pentanonehydrochloride

Using tert-butyl5-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-5-oxopentyl(2-phenylethyl)carbamate(280 mg) obtained in Reference Example 48 according to the same methodas that of Example 1, the title compound (220 mg) was obtained ascolorless crystals.

¹H NMR(400 MHz, DMSO-d₆) δ 1.60–1.73(4H, m), 2.18(3H, s), 2.90–3.01(6H,m), 3.05–3.10(2H, m), 3.16(2H, t, J=8.4 Hz), 4.13(2H, t, J=8.4 Hz),7.21–7.34(5H, m), 7.81(1H, s), 7.82(1H, d, J=8 Hz), 8.08(1H, t, J=8 Hz),9.21(2H, br.s). IR (KBr) νcm⁻¹: 3438, 2783, 1679, 1662, 1604, 1495,1440, 1401, 1334, 1260.

Example 931-(1-Acetyl-2,3-dihydro-1H-indol-5-yl)-5-[[2-(2-chlorophenyl)ethyl]amino]-1-pentanonehydrochloride

Using tert-butyl5-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-5-oxopentyl[2-(2-chlorophenyl)ethyl]carbamate(330 mg) obtained in Reference Example 49 according to the same methodas that of Example 1, the title compound (175 mg) was obtained ascolorless crystals having a melting point of 185 to 186° C.

¹H NMR(400 MHz, DMSO-d₆) δ 1.63–1.74(4H, m), 2.17(3H, s), 2.92–3.01(4H,m), 3.08–3.18(6H, m), 4.13(2H, t, J=8 Hz), 7.26–7.34(2H, m), 7.39(1H, d,d, J=7, 2 Hz), 7.44(1H, d, d, J=7, 2 Hz), 7.81(1H, s), 7.82(1H, d, J=8Hz), 8.07(1H, d, J=8 Hz), 9.35(2H, s). IR (KBr) νcm⁻¹: 3434, 2947, 2782,1683, 1660, 1441, 1403, 1335, 1259.

Example 941-(2,3-Dihydro-1H-indol-5-yl)-5-[[2-(2-methoxyphenyl)ethyl]amino]-1-pentanonedihydrochloride

Using tert-butyl5-(2,3-dihydro-1H-indol-5-yl)-5-oxopentyl[2-(2-methoxyphenyl)ethyl]carbamate(452 mg) obtained in Reference Example 50 according to the same methodas that of Example 1, the title compound (330 mg) was obtained ascolorless crystals having a melting point of 164 to 165° C.

¹H NMR(400 MHz, DMSO-d₆) δ 1.58–1.72(4H, m), 2.93(6H, t, J=7 Hz),2.99–3.03(2H, m), 3.05(2H, t, J=8.2 Hz), 3.60(2H, t, J=8.2 Hz), 3.78(3H,s), 6.81(1H, d, J=8 Hz), 6.89(1H, t, J=7 Hz), 6.98(1H, d, J=7 Hz),7.17(1H, d, J=7 Hz), 7.24(1H, t, J=7 Hz), 7.74(1H, d, J=8 Hz), 7.75(1H,s), 9.06(4H, br.s). IR (KBr) νcm⁻¹: 3429, 2950, 2781, 2460, 1694, 1497,1247.

Example 951-(2,3-Dihydro-1H-indol-5-yl)-5-[[2-(2-methoxyphenyl)ethyl]amino]-1-pentanonedihydrochloride

Using tert-butyl5-(2,3-dihydro-1H-indol-5-yl)-5-oxopentyl[2-(2-methoxyphenyl)ethyl]carbamate(120 mg) obtained in Reference Example 51 according to the same methodas that of Example 1, the title compound (106 mg) was obtained ascolorless crystals having a melting point of 150 to 151° C.

¹H NMR(400 MHz, DMSO-d₆) δ 1.60–1.67(4H, m), 2.80(3H, s), 2.85–3.01(10H,m), 3.44(2H, t, J=8.4 Hz), 3.78(3H, s), 6.46(1H, d, J=8.3 Hz), 6.89(1H,t, J=7.4 Hz), 6.98(1H, d, J=8.3 Hz), 7.16(1H, d, J=7.4 Hz), 7.23(1H, t,J=8.3 Hz), 7.60(1H, s), 7.72(1H, d, J=8.3 Hz), 9.10(3H, br.s). IR (KBr)νcm⁻¹: 3436, 2583, 2424, 1675, 1600, 1494, 1464, 1249, 1032, 760.

Example 961-(1-Ethyl-2,3-dihydro-1H-indol-5-yl)-5-[[2-(2-methoxyphenyl)ethyl]amino]-1-pentanonedihydrochloride

Using tert-butyl5-(1-ethyl-2,3-dihydro-1H-indol-5-yl)-5-oxopentyl[2-(2-methoxyphenyl)ethyl]carbamate(165 mg) obtained in Reference Example 52 according to the same methodas that of Example 1, the title compound (145 mg) was obtained ascolorless crystals having a melting point of 131 to 133° C.

¹H NMR(400 MHz, DMSO-d₆) δ 1.08(3H, t, J=7.2 Hz), 1.61–1.69(4H, m),2.84–3.01(10H, m), 3.23(2H, q, J=7.2 Hz), 3.48(2H, t, J=8.4 Hz),3.78(3H, s), 6.45(1H, d, J=8.4 Hz), 6.89(1H, t, J=7 Hz), 6.98(1H, d,J=8.4 Hz), 7.16(1H, d, J=7 Hz), 7.23(1H, t, J=8.4 Hz), 7.59(1H, s),7.70(1H, d, J=8.4 Hz), 9.11(3H, br). IR (KBr) νcm⁻: 3426, 2777, 2458,1697, 1602, 1496, 1442, 1317, 1248, 1051, 763.

Example 971-[1-(3-Hydroxypropyl)-2,3-dihydro-1H-indol-5-yl]-5-[[2-(2-methoxyphenyl)ethyl]amino]-1-pentanonedihydrochloride

Using tert-butyl5-[1-(3-hydroxypropyl)-2,3-dihydro-1H-indol-5-yl]-5-oxopentyl[2-(2-methoxyphenyl)ethyl]carbamate(60 mg) obtained in Reference Example 53 according to the same method asthat of Example 1, the title compound (55 mg) was obtained as paleyellow amorphous powders.

¹H NMR(400 MHz, CD₃OD) δ 1.68–1.79(4H, m), 1.84(2H, t, J=7.4 Hz),1.90–1.99(2H, m), 2.92–3.18(8H, m), 3.35(2H, t, J=6 Hz), 3.57–3.70(4H,m), 3.82(3H, s), 4.82(4H, s), 6.63(1H, d, J=8 Hz), 6.88(1H, t, J=7 Hz),6.95(1H, d, J=8 Hz), 7.16(1H, d, J=7.4 Hz), 7.23(1H, t, J=7.4 Hz),7.69(1H, s), 7.79(1H, d, J=7 Hz). IR (neat) νcm⁻¹: 3402, 2920, 1693,1602, 1496, 1443, 1247, 760.

Example 98 Ethyl[5-(5-[[2-(2-methoxyphenyl)ethyl]amino]pentanoyl)-2,3-dihydro-1H-indol-1-yl]acetatedihydrochloride

Using ethyl[5-(5-[(tert-butoxycarbonyl)[2-(2-methoxyphenyl)ethyl]amino]pentanoyl)-2,3-dihydro-1H-indol-1-yl]acetate(270 mg) obtained in Reference Example 54 according to the same methodas that of Example 1, the title compound (255 mg) was obtained as paleyellow amorphous powders.

¹H NMR(400 MHz, CD₃OD) δ 1.26(3H, t, J=7 Hz), 1.70–1.80(4H, m),2.96–3.21(10H, m), 3.82–3.85(2H, m), 3.81(3H, s), 3.86(2H, s), 4.18(2H,q, J=7.2 Hz), 4.84(3H, s), 6.37(1H, d, J=8.34 Hz), 6.91(1H, t, J=7.4Hz), 6.98(1H, d, J=8.3 Hz), 7.20(1H, d, J=7.4 Hz), 7.26(1H, t, J=8.3Hz), 7.68(1H, s), 7.76(1H, d, J=8.3 Hz). IR (KBr) νcm⁻¹: 3420, 2774,1736, 1663, 1603, 1496, 1443, 1248, 1182, 1026, 759.

Example 99N-Ethyl-5-(5-[[2-(2-methoxyphenyl)ethyl]amino]pentanoyl)-1-indolinecarboxamidehydrochloride

Using tert-butyl5-[1-[(ethylamino)carbonyl]-2,3-dihydro-1H-indol-5-yl]-5-oxopentyl[2-(2-methoxyphenyl)ethyl]carbamate(250 mg) obtained in Reference Example 55 according to the same methodas that of Example 1, the title compound (205 mg) was obtained ascolorless crystals having a melting point of 185 to 186° C.

¹H NMR(400 MHz, DMSO-d₆) δ 1.08(3H, t, J=7.3 Hz), 1.63–1.70(4H, m),2.92–3.03(8H, m), 3.11–3.18(4H, m), 3.79(3H, s), 3.93(2H, t, J=8.4 Hz),6.87–6.91(2H, m), 6.98(1H, d, J=8.4 Hz), 7.16(1H, d, J=7.4 Hz), 7.24(1H,t, J=8.4 Hz), 7.73(1H, s), 7.76(1H, d, J=8.4 Hz), 7.88(1H, d, J=8.4 Hz),9.06(2H, s). IR (KBr) νcm⁻¹: 3315, 2773, 1667, 1604, 1526, 1494, 1442,1319, 1245, 754.

Example 1001-(1-Acetyl-2,3-dihydro-1H-indol-5-yl)-5-[[2-(2-methoxyphenyl)ethyl](methyl)amino]-1-pentanonehydrochloride

Using 1-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-5-chloropentan-1-oneobtained in Reference Example 11 andN-[2-(2-methoxyphenyl)ethyl]-N-methylamine according to the same methodas that of Example 9, the title compound was obtained as yellowamorphous powders.

¹H NMR(free base; 400 MHz, CDCl₃) δ 1.54–1.61(2H, m), 1.70–1.78(2H, m),2.25(3H, s), 2.31(3H, s), 2.46(2H, t, J=7.5 Hz), 2.55–2.59(2H, m),2.76–2.80(2H, m), 2.94(2H, t, J=7.3 Hz), 3.23(2H, t, J=8.3 Hz), 3.81(3H,s), 4.11(2H, t, J=8.3 Hz), 6.82–6.87(2H, m), 7.12–7.19(2H, m),7.81–7.84(2H, m), 8.23(1H, d, J=8.3 Hz). IR (free base; neat) νcm⁻¹:1673, 1603, 1493, 1440, 1394, 1329, 1244.

Example 1011-(1-Acetyl-2,3-dihydro-1H-indol-5-yl)-5-[[2-(2-chlorophenyl)ethyl](methyl)amino]-1-pentanonehydrochloride

Using 1-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-5-chloropentan-1-oneobtained in Reference Example 11 andN-[2-(2-chlorophenyl)ethyl]-N-methylamine according to the same methodas that of Example 9, the title compound was obtained as yellowamorphous powders.

¹H NMR(free base; 400 MHz, CDCl₃) δ 1.54–1.61(2H, m), 1.70–1.77(2H, m),2.24(3H, s), 2.33(3H, s), 2.47(2H, t, J=6.3 Hz), 2.61(2H, t, J=7 Hz),2.88–2.95(4H, m), 3.22(2H, t, J=7.5 Hz), 4.10(2H, t, J=7.5 Hz),7.11–7.33(4H, m), 7.79–7.83(2H, m), 8.22(1H, d, J=8.5 Hz). IR (freebase; neat) νcm⁻¹: 1673, 1604, 1489, 1440, 1391, 1330, 1256.

Example 1021-(1-Acetyl-2,3-dihydro-1H-indol-5-yl)-6-[[2-(2-methoxyphenyl)ethyl]amino]-1-hexanonehydrochloride

Using 1-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-6-bromo-1-hexanone (388 mg)obtained in Reference Example 12 and 2-(2-methoxyphenyl)ethylamine (378mg) according to the same method as that of Example 9, the titlecompound (140 mg) was obtained as colorless crystals having a meltingpoint of 186 to 187° C.

¹H NMR(free base; 400 MHz, CDCl₃) δ 1.35–1.43(2H, m), 1.49–1.56(2H, m),1.64(1H, br.s), 1.69–1.76(2H, m), 2.24(3H, s), 2.68(2H, t, J=7 Hz),2.83(4H, br.s), 2.91(2H, t, J=7 Hz), 3.22(2H, t, J=8.3 Hz), 3.81(3H, s),4.11(2H, t, J=8.3 Hz), 6.83–6.88(2H, m), 7.13–7.20(2H, m), 7.79–7.82(2H,m), 8.23(1H, d, J=8.3 Hz). IR (free base; neat) νcm⁻¹: 1673, 1602, 1493,1440, 1394, 1329, 1243.

Example 1031-(1-Acetyl-2,3-dihydro-1H-indol-5-yl)-6-[[2-(2-chlorophenyl)ethyl]amino]-1-hexanonehydrochloride

Using 1-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-6-bromo-1-hexanone (270 mg)obtained in Reference Example 12 and 2-(2-chlorophenyl)ethylamine (311mg) according to the same method as that of Example 9, the titlecompound (128 mg) was obtained as colorless crystals having a meltingpoint of 182 to 183° C.

¹H NMR(free base; 400 MHz, CDCl₃) δ 1.38–1.44(2H, m), 1.47(1H, br.s),1.50–1.57(2H, m), 1.70–1.77(2H, m), 2.24(3H, s), 2.66(2H, t, J=7.5 Hz),2.85–2.94(6H, m), 3.22(2H, t, J=8 Hz), 4.10(2H, t, J=8 Hz),7.14–7.35(4H, m), 7.79–7.82(2H, m), 8.22(1H, d, J=8.5 Hz). IR (freebase; neat) νcm⁻¹: 1673, 1604, 1489, 1441, 1395, 1330, 1262.

Example 1041-(1-Acetyl-2,3-dihydro-1H-indol-5-yl)-6-[[2-(2-methoxyphenyl)ethyl](methyl)amino]-1-hexanonehydrochloride

Using 1-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-6-bromo-1-hexanone obtainedin Reference Example 12 and N-[2-(2-methoxyphenyl)ethyl]-N-methylamineaccording to the same method as that of Example 9, the title compoundwas obtained as yellow amorphous powders.

¹H NMR(free base; 400 MHz, CDCl₃) δ 1.36–1.42(2H, m), 1.51–1.58(2H, m),1.70–1.78(2H, m), 2.24(3H, s), 2.31(3H, s), 2.42(2H, t, J=7.5 Hz),2.55–2.59(2H, m), 2.76–2.80(2H, m), 2.92(2H, t, J=7.5 Hz), 3.21(2H, t,J=8.3 Hz), 3.81(3H, s), 4.09(2H, t, J=8.3 Hz), 6.82–6.89(2H, m),7.12–7.19(2H, m), 7.79–7.83(2H, m), 8.23(1H, d,J=8.3 Hz). IR (free base;neat) νcm⁻¹: 1674, 1603, 1493, 1440, 1394, 1329, 1244.

Example 1051-(1-Acetyl-2,3-dihydro-1H-indol-5-yl)-6-[[2-(2-chlorophenyl)ethyl](methyl)amino]-1-hexanonehydrochloride

Using 1-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-6-bromo-1-hexanone obtainedin Reference Example 12 and N-[2-(2-chlorophenyl)ethyl]-N-methylamineaccording to the same method as that of Example 9, the title compoundwas obtained as colorless crystals having a melting point of 177 to 178°C.

¹H NMR(free base; 400 MHz, CDCl₃) δ 1.35–1.42(2H, m), 1.50–1.58(2H, m),1.70–1.78(2H, m), 2.25(3H, s), 2.33(3H, s), 2.43(2H, t, J=7 Hz),2.58–2.62(2H, m), 2.88–2.95(4H, m), 3.23(2H, t, J=8 Hz), 4.10(2H, t, J=8Hz), 7.11–7.33(4H, m), 7.80–7.83(2H, m), 8.22(1H, d, J=8.5 Hz). IR (freebase; neat) νcm⁻¹: 1674, 1604, 1489, 1441, 1394, 1329, 1246.

Example 1066-[5-[(2-Phenylethyl)amino]pentanoyl]-2H-1,4-benzoxazin-3(4H)-onehydrochloride

Using tert-butyl5-oxo-5-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)pentyl(2-phenylethyl)carbamateobtained in Reference Example 41 according to the same method as that ofExample 1, the title compound was obtained as colorless amorphouspowders.

¹H NMR(300 MHz, DMSO-d₆) δ 1.68 (4H, br.), 2.96–3.01(6H, m), 3.10(2H,br.s), 4.69(2H, s), 7.05(1H, d, J=8.4 Hz), 7.26–7.37(5H, m), 7.53(1H, d,J=1.8 Hz), 7.63(1H, dd, J=8.4, 1.5 Hz), 9.13(2H, br), 10.95(1H, s).[M+H]⁺ (ESI+)=353, HPLC purity 94% (220 nm)

Example 107N-(5-{5-[[2-(2-chlorophenyl)ethyl](methyl)amino]pentanoyl}-2,3-dihydro-1H-inden-2-yl)methanesulfonamidehydrochloride

UsingN-[5-(5-chloropentanoyl)-2,3-dihydro-1H-inden-2-yl]methanesulfonamideobtained in Reference Example 233 andN-[2-(2-chlorophenyl)ethyl]-N-methylamine according to the same methodas that of Example 9, the title compound was obtained as colorlessamorphous powders.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.52–1.81 (4H, m), 2.33 (3H, s),2.47 (2H, t, J=7.4 Hz), 2.60 (2H, m), 2.64–2.98 (6H, m), 3.01 (3H, s),3.35 (2H, dd, J=16.4, 7.2 Hz), 4.30 (1H, m), 5.08 (1H, br), 7.07–7.34(5H, m), 7.78 (2H, m).

Example 1086-(5-[[2-(2-Ethoxyphenyl)ethyl]amino]pentanoyl)-2H-1,4-benzoxazin-3(4H)-onehydrochloride

Using tert-butyl2-(2-ethoxyphenyl)ethyl[5-oxo-5-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)pentyl]carbamateobtained in Reference Example 42 according to the same method as that ofExample 1, the title compound was obtained as colorless amorphouspowders.

¹H NMR(300 MHz, DMSO-d₆) δ 1.67(4H, br.), 2.95–3.02(8H, m), 3.52(2H,br.s), 3.80(3H, s), 4.69(2H, s), 6.89–6.99(1H, m), 6.99–7.04(2H, m),7.20–7.28(2H, m), 7.54(1H, d, J=1.8 Hz), 7.63(1H, dd, J=8.4, 1.5 Hz),9.11(2H, br.), 10.96(1H,s). MS m/z: 397 [M+H]⁺

Example 1096-(5-[[2-(2-Flurophenyl)ethyl]amino]pentanoyl)-2H-1,4-benzoxazin-3(4H)-onehydrochloride

Using tert-butyl2-(2-flurohenyl)ethyl[5-oxo-5-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)pentyl]carbamateobtained in Reference Example 43 according to the same method as that ofExample 1, the title compound was obtained as colorless amorphouspowders.

¹H NMR(300 MHz, DMSO-d₆) δ 1.67(4H, m), 3.00–3.04(6H, m), 3.09(2H, m),4.69(2H, s), 7.06(1H, d, J=8.1 Hz), 7.17–7.24(2H, m), 7.30–7.38(2H, m),7.51(1H, d, J=1.8 Hz), 7.63(1H, dd, J=8.4, 1.8 Hz), 9.04(2H, br.),10.93(1H, s). MS m/z: 371 [M+H]⁺

Example 1106-(5-[[2-(2-Chlorophenyl)ethyl]amino]pentanoyl)-2H-1,4-benzoxazin-3(4H)-onehydrochloride

Using tert-butyl2-(2-chlorophenyl)ethyl[5-oxo-5-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)pentyl]carbamateobtained in Reference Example 44 according to the same method as that ofExample 1, the title compound was obtained as colorless amorphouspowders.

¹H NMR(300 MHz, DMSO-d₆) δ 1.68(4H, m), 2.98–3.02(4H, m), 3.11(4H, br.),4.69(2H, s), 7.04(1H, d, J=. 8.1Hz), 7.31–7.49(4H, m), 7.52(1H, d, J=1.5Hz), 7.63(1H, dd, J=8.3, 1.4 Hz), 9.13(2H, br.), 10.93(1H, s). MS m/z:387 [M+H]⁺

Example 1116-(5-[[2-(3-Methoxyphenyl)ethyl]amino]pentanoyl)-2H-1,4-benzoxazin-3(4H)-onehydrochloride

Using tert-butyl2-(3-methoxyphenyl)ethyl[5-oxo-5-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)pentyl]carbamateobtained in Reference Example 45 according to the same method as that ofExample 1, the title compound was obtained as colorless amorphouspowders.

¹H NMR(300 MHz, DMSO-d₆) δ 1.67(4H, br.), 2.92–3.02(6H, m), 3.13(2H,br.), 3.75(3H, s), 4.69(2H, s), 6.82–6.84(3H, m), 7.05(1H, d, J=8.4 Hz),7.23–7.28(1H, m), 7.52(1H, d, J=2.1 Hz), 7.63(1H, dd, J=8.3, 2.0 Hz),9.03(2H, br.), 10.93(1H, s). MS m/z: 383 [M+H]⁺

Example 1126-(5-[[2-(3-Ethoxyphenyl)ethyl]amino]pentanoyl)-2H-1,4-benzoxazin-3(4H)-onehydrochloride

Using tert-butyl2-(3-ethoxyphenyl)ethyl[5-oxo-5-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)pentyl]carbamateobtained in Reference Example 46 according to the same method as that ofExample 1, the title compound was obtained as colorless amorphouspowders.

¹H NMR(300 MHz, DMSO-d₆) δ 1.32(3H, t, J=6.9 Hz), 1.67(4H, br.),2.91–3.02(6H, m), 3.11(2H, br.), 4.01(2H, q, J=6.9 Hz), 4.68(2H, s),6.80–6.82(3H, m), 7.05(1H, d, J=8.4 Hz), 7.21–7.26(1H, m), 7.52(1H, d,J=1.8 Hz), 7.63(1H, dd, J=8.3, 1.4 Hz), 9.02(2H, br.), 10.93(1H, s). MSm/z: 397 [M+H]⁺

Example 1136-(5-[[2-(3-Flurophenyl)ethyl]amino]pentanoyl)-2H-1,4-benzoxazin-3(4H)-onehydrochloride

Using tert-butyl2-(3-flurophenyl)ethyl[5-oxo-5-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)pentyl]carbamateobtained in Reference Example 56 according to the same method as that ofExample 1, the title compound was obtained as colorless amorphouspowders.

¹H NMR(300 MHz, DMSO-d₆) δ 1.67(4H, br.), 2.95–3.03(6H, m), 3.14(2H,br.), 4.69(2H, s), 7.06(1H, d, J=8.4 Hz), 7.09–7.17(3H, m),7.34–7.42(1H, m), 7.52(1H, d, J=1.8 Hz), 7.63(1H, dd, J=8.3, 1.4 Hz),9.04(2H, br.), 10.93(1H, s). MS m/z: 371 [M+H]⁺

Example 1146-(5-[[2-(3-Chlorophenyl)ethyl]amino]pentanoyl)-2H-1,4-benzoxazin-3(4H)-onehydrochloride

Using tert-butyl2-(3-chlorophenyl)ethyl[5-oxo-5-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)pentyl]carbamateobtained in Reference Example 57 according to the same method as that ofExample 1, the title compound was obtained as colorless amorphouspowders.

¹H NMR(300 MHz, DMSO-d₆) δ 1.67(4H, br.), 2.95–3.02(6H, m), 3.13(2H,br.), 4.69(2H, s), 7.06(1H, d, J=8.1 Hz), 7.24–7.38(4H, m), 7.52(1H, d,J=1.8 Hz), 7.63(1H, dd, J=8.3, 1.1 Hz), 9.06(2H, br.), 10.94(1H, s). MSm/z: 387 [M+H]⁺

Example 1156-[5-[Methyl(2-phenylethyl)amino]pentanoyl]-2H-1,4-benzoxazin-3(4H)-onehydrochloride

Using 6-(5-chloropentanoyl)-2H-1,4-benzoxazin-3(4H)-one obtained inReference Example 7 and N-methyl-N-(2-phenylethyl)amine according to thesame method as that of Example 9, the title compound was obtained ascolorless amorphous powders.

¹H NMR(200 MHz, DMSO-d₆) δ 1.68(4H, br.), 2.81(3H, s), 2.98–3.44(8H, m),4.67(2H, s), 7.04(1H, d, J=8.6 Hz), 7.25–7.51(5H, m), 7.49(1H, d, J=2.0Hz), 7.62(1H, dd, J=8.6, 2.0 Hz), 9.93(1H, br.s), 10.88(1H, s). MS m/z:381 [M+H]⁺

Example 1166-[5-[[2-(2-Methoxyphenyl)ethyl](methyl)amino]pentanoyl]-2H-1,4-benzoxazin-3(4H)-onehydrochloride

Using 6-(5-chloropentanoyl)-2H-1,4-benzoxazin-3(4H)-one obtained inReference Example 7 and N-[2-(2-methoxyphenyl)ethyl]-N-methylamineaccording to the same method as that of Example 9, the title compoundwas obtained as colorless amorphous powders.

¹H NMR(200 MHz, DMSO-d₆) δ 1.68(4H, br.), 2.82(3H, d, J=3.4 Hz),2.94–3.23(8H, br.), 3.82(3H, s), 4.67(2H, s), 6.92(1H, t, J=4.9 Hz),7.01(1H, d, J=8.4 Hz), 7.04(1H, d, J=8.2 Hz), 7.21–7.29(2H, m), 7.50(1H,d, J=1.4 Hz), 7.62(1H, dd, J=5.7, 1.3 Hz), 9.97(1H, br.s), 10.89(1H, s).MS m/z: 397 [M+H]⁺

Example 1176-[5-[[2-(2-Fluorophenyl)ethyl](methyl)amino]pentanoyl]-2H-1,4-benzoxazin-3(4H)-onehydrochloride

Using 6-(5-chloropentanoyl)-2H-1,4-benzoxazin-3(4H)-one obtained inReference Example 7 and N-[2-(2-fluorophenyl)ethyl]-N-methylamineaccording to the same method as that of Example 9, the title compoundwas obtained as colorless amorphous powders.

¹H NMR(200 MHz, DMSO-d₆) δ 1.68(4H, br.), 2.82(3H, d, J=4.8 Hz),2.98–3.34(8H, br.), 4.67(2H, s), 7.04(1H, d, J=8.0 Hz), 7.15–7.24(2H,m), 7.28–7.40(2H, m), 7.51(1H, d, J=1.8 Hz), 7.62(1H, dd, J=8.6, 2.2Hz), 10.26(1H, br.s), 10.89(1H, s). MS m/z: 385 [M+H]⁺

Example 1186-[5-[[2-(2-Chlorophenyl)ethyl](methyl)amino]pentanoyl]-2H-1,4-benzoxazin-3(4H)-onehydrochloride

Using 6-(5-chloropentanoyl)-2H-1,4-benzoxazin-3(4H)-one obtained inReference Example 7 and N-[2-(2-chlorophenyl)ethyl]-N-methylamineaccording to the same method as that of Example 9, the title compoundwas obtained as colorless amorphous powders.

¹H NMR(200 MHz, DMSO-d₆) δ 1.69(4H, br.), 2.83(3H, s), 2.97(2H, t, J=7Hz), 3.18(6H, m), 4.67(2H, s), 7.04(1H, d, J=8.2 Hz), 7.30–7.38(2H, m),7.43–7.51(2H, m), 7.59(1H, d, J=1.8 Hz), 7.62(1H, dd, J=8.4, 1.8 Hz),10.36(1H, br.s), 10.87(1H, s). MS m/z: 401 [M+H]⁺

Example 1196-[5-[[2-(3-Methoxyphenyl)ethyl](methyl)amino]pentanoyl]-2H-1,4-benzoxazin-3(4H)-onehydrochloride

Using 6-(5-chloropentanoyl)-2H-1,4-benzoxazin-3(4H)-one obtained inReference Example 7 and N-[2-(3-methoxyphenyl)ethyl]-N-methylamineaccording to the same method as that of Example 9, the title compoundwas obtained as colorless amorphous powders.

¹H NMR(200 MHz, DMSO-d₆) δ 1.68(4H, br.), 2.82(3H, d, J=3.2 Hz),2.96–3.34(8H, br.), 3.76(3H, s), 4.67(2H, s), 6.81(1H, d, J=1.6 Hz),6.86(2H, d, J=5.6 Hz), 7.04(1H, d, J=5.8 Hz), 7.25(1H, t, J=5.2 Hz),7.50(1H, d, J=1.6 Hz), 7.61(1H, dd, J=5.6, 1.4 Hz), 9.68(1H, br.s),10.89(1H, s). MS m/z: 397 [M+H]⁺

Example 1206-[5-[[2-(3-Fluorophenyl)ethyl](methyl)amino]pentanoyl]-2H-1,4-benzoxazin-3(4H)-onehydrochloride

Using 6-(5-chloropentanoyl)-2H-1,4-benzoxazin-3(4H)-one obtained inReference Example 7 and N-[2-(3-fluorophenyl)ethyl]-N-methylamineaccording to the same method as that of Example 9, the title compoundwas obtained as colorless amorphous powders.

¹H NMR(300 MHz, DMSO-d₆) δ 1.68(4H, br.), 2.82(3H, d, J=4.5 Hz),2.98–3.36(8H, br.), 4.67(2H, s), 7.02–7.19(4H, m), 7.34–7.42(1H, m),7.50(1H, d, J=2.1 Hz), 7.63(1H, dd, J=8.7, 2.1 Hz), 9.69(1H, br.s),10.88(1H, s). MS m/z: 385 [M+H]⁺

Example 1216-[5-[[2-(3-Chlorophenyl)ethyl](methyl)amino]pentanoyl]-2H-1,4-benzoxazin-3(4H)-onehydrochloride

Using 6-(5-chloropentanoyl)-2H-1,4-benzoxazin-3(4H)-one obtained inReference Example 7 and N-[2-(3-chlorophenyl)ethyl]-N-methylamineaccording to the same method as that of Example 9, the title compoundwas obtained as colorless amorphous powders.

¹H NMR(200 MHz, DMSO-d₆) δ 1.68(4H, br.), 2.81(3H, d, J=4.8 Hz),3.03–3.63(8H, br.), 4.67(2H, s), 7.04(1H, d, J=8.4 Hz), 7.25–7.42(4H,m), 7.51(1H, d, J=1.8 Hz), 7.62(1H, dd, J=8.4, 1.8 Hz), 10.06(1H, br.s),10.90(1H, s). MS m/z: 401 [M+H]⁺

Example 1226-[6-[[2-(2-Methoxyphenyl)ethyl](methyl)amino]hexanoyl]-2H-1,4-benzoxazin-3(4H)-onehydrochloride

Using 6-(6-bromohexanoyl)-2H-1,4-benzoxazin-3(4H)-one obtained inReference Example 8 and N-[2-(2-methoxyphenyl)ethyl]-N-methylamineaccording to the same method as that of Example 9, the title compoundwas obtained as colorless amorphous powders.

¹H NMR(200 MHz, DMSO-d₆) δ 1.31–1.41(2H, m), 1.61–1.79(4H, m), 2.79(3H,d, J=4.8 Hz), 2.92–3.42(8H, br.), 3.81(3H, s), 4.67(2H, s),6.87–7.05(3H, m), 7.20–7.30(2H, m), 7.50(1H, d, J=1.8 Hz), 7.61(1H, dd,J=8.2, 2.0 Hz), 10.13(1H, br.s), 10.85(1H, s). MS m/z: 411 [M+H]⁺

Example 1236-[6-[[2-(2-Fluorophenyl)ethyl](methyl)amino]hexanoyl]-2H-1,4-benzoxazin-3(4H)-onehydrochloride

Using 6-(6-bromohexanoyl)-2H-1,4-benzoxazin-3(4H)-one obtained inReference Example 8 and N-[2-(2-fluorophenyl)ethyl]-N-methylamineaccording to the same method as that of Example 9, the title compoundwas obtained as colorless amorphous powders.

¹H NMR(200 MHz, DMSO-d₆) δ 1.32–1.42(2H, m), 1.61–1.78(4H, m), 2.81(3H,s), 2.92–3.30(8H, br.), 4.67(2H, s), 7.03(1H, d, J=8.4 Hz),7.05–7.24(2H, m), 7.29–7.43(2H, m), 7.51(1H, d, J=1.8 Hz), 7.61(1H, dd,J=8.4, 1.8 Hz), 10.60(1H, br.s), 10.90(1H, s). MS m/z: 399 [M+H]⁺

Example 1246-[6-[[2-(2-Chlorophenyl)ethyl](methyl)amino]hexanoyl]-2H-1,4-benzoxazin-3(4H)-onehydrochloride

Using 6-(6-bromohexanoyl)-2H-1,4-benzoxazin-3(4H)-one obtained inReference Example 8 and N-[2-(2-chlorophenyl)ethyl]-N-methylamineaccording to the same method as that of Example 9, the title compoundwas obtained as colorless amorphous powders.

¹H NMR(200 MHz, DMSO-d₆) δ 1.33–1.43(2H, m), 1.61–1.78(4H, m), 2.85(3H,d, J=4.8 Hz), 2.96(2H, t, J=7 Hz), 3.12–3.21(6H, m), 4.66(2H, s),7.03(1H, d, J=8.4 Hz), 7.27–7.37(2H, m), 7.41–7.48(2H, m), 7.50(1H, d,J=2.0 Hz), 7.60(1H, dd, J=8.2, 2.0 Hz), 10.24(1H, br.s), 10.87(1H, s).MS m/z: 415 [M+H]⁺

Example 1256-[6-[[2-(3-Methoxyphenyl)ethyl](methyl)amino]hexanoyl]-2H-1,4-benzoxazin-3(4H)-onehydrochloride

Using 6-(6-bromohexanoyl)-2H-1,4-benzoxazin-3(4H)-one obtained inReference Example 8 and N-[2-(3-methoxyphenyl)ethyl]-N-methylamineaccording to the same method as that of Example 9, the title compoundwas obtained as colorless amorphous powders.

¹H NMR(200 MHz, DMSO-d₆) δ 1.34(2H, br.), 1.61–1.78(4H, m), 2.79(3H, d,J=3.8 Hz), 2.96–3.26(8H, m), 3.75(3H, s), 4.67(2H, s), 6.84(3H, t, J=6.9Hz), 7.03(1H, d, J=8.4 Hz), 7.25(1H, t, J=8.0 Hz), 7.52(1H, s), 7.61(1H,d, J=7.4 Hz), 10.5(1H, br.s), 10.91(1H, s). MS m/z: 411 [M+H]⁺

Example 1266-[6-[[2-(3-Fluorophenyl)ethyl](methyl)amino]hexanoyl]-2H-1,4-benzoxazin-3(4H)-onehydrochloride

Using 6-(6-bromohexanoyl)-2H-1,4-benzoxazin-3(4H)-one obtained inReference Example 8 and N-[2-(3-fluorophenyl)ethyl]-N-methylamineaccording to the same method as that of Example 9, the title compoundwas obtained as colorless amorphous powders.

¹H NMR(300 MHz, CD₃OD) δ 1.44–1.52(2H, br.), 1.73–1.86(4H, m), 2.94(3H,s), 3.00–3.19(4H, m), 3.23–3.49(4H, m), 4.67(2H, s), 6.98–7.15(4H, m),7.33–7.40(1H, m), 7.54(1H, d, J=2.1 Hz), 7.67(1H, dd, J=8.4 Hz, 2.2 Hz).MS m/z: 399 [M+H]⁺

Example 1276-[6-[[2-(3-Chlorophenyl)ethyl](methyl)amino]hexanoyl]-2H-1,4-benzoxazin-3(4H)-onehydrochloride

Using 6-(6-bromohexanoyl)-2H-1,4-benzoxazin-3(4H)-one obtained inReference Example 8 and N-[2-(3-chlorophenyl)ethyl]-N-methylamineaccording to the same method as that of Example 9, the title compoundwas obtained as colorless amorphous powders.

¹H NMR(200 MHz, DMSO-d₆) δ 1.33–1.40(2H, br.), 1.62–1.76(4H, m),2.80(3H, d, J=4.8 Hz), 2.93–3.63(8H, m), 4.67(2H, s), 7.03(1H, d, J=8.1Hz), 7.26–7.30(4H, m), 7.51(1H, d, J=1.8 Hz), 7.61(1H, d, J=8.4 Hz, 2.1Hz), 10.5(1H, br.s), 10.9(1H, s). MS m/z: 415 [M+H]⁺

Example 1286-[5-[[2-(2-Ethoxyphenyl)ethyl](methyl)amino]pentanoyl]-2H-1,4-benzoxazin-3(4H)-onehydrochloride

Using 6-(5-chloropentanoyl)-2H-1,4-benzoxazin-3(4H)-one obtained inReference Example 7 and N-[2-(2-ethoxyphenyl)ethyl]-N-methylamineaccording to the same method as that of Example 9, the title compoundwas obtained as colorless amorphous powders.

¹H NMR(free base; 200 MHz, CDCl₃) δ 1.41(3H, t, J=6.9 Hz), 1.56–1.63(2H,m), 1.70–1.78(2H, m), 2.33(3H, s), 2.47(2H, t, J=7.5), 2.57–2.62(2H, m),2.77–2.84(2H, m), 2.93(2H, t, J=7.3H), 3.99–4.06(2H, m), 4.68(2H, s),5.60(1H, br.s), 6.80–6.89(2H, m), 7.00(1H, d, J=8.4 Hz), 7.10–7.26(2H,m), 7.51(1H, d, J=2.4 Hz), 7.61(1H, dd, J=8.4, 2.1 Hz). MS m/z: 411[M+H]⁺

Example 1296-[5-[[2-(3-Ethoxyphenyl)ethyl](methyl)amino]pentanoyl]-2H-1,4-benzoxazin-3(4H)-onehydrochloride

Using 6-(5-chloropentanoyl)-2H-1,4-benzoxazin-3(4H)-one obtained inReference Example 7 and N-[2-(3-ethoxyphenyl)ethyl]-N-methylamineaccording to the same method as that of Example 9, the title compoundwas obtained as colorless amorphous powders.

¹H NMR(free base; 300 MHz, CDCl₃) δ 1.40(3H, t, J=6.9 Hz), 1.53–1.61(2H,m), 1.69–1.76(2H, s), 2.30(3H, s), 2.45(2H, t, J=7.4 Hz), 2.57–2.63(2H,m), 2.69–2.76(2H, m), 2.91(2H, t, J=7.2H), 4.00(2H, t, J=6.9 Hz),4.67(2H, s), 5.60(1H, br.s), 6.69–6.78(3H, m), 6.99(1H, d, J=8.1 Hz),7.16(1H, t, J=8.0 Hz), 7.52(1H, d, J=1.8 Hz), 7.58(1H, dd, J=8.4, 2.1Hz). MS m/z: 411 [M+H]⁺

Example 1306-[6-[[2-(2-Ethoxyphenyl)ethyl](methyl)amino]hexanoyl]-2H-1,4-benzoxazin-3(4H)-onehydrochloride

Using 6-(6-bromohexanoyl)-2H-1,4-benzoxazin-3(4H)-one obtained inReference Example 8 and N-[2-(2-ethoxyphenyl)ethyl]-N-methylamineaccording to the same method as that of Example 9, the title compoundwas obtained as colorless amorphous powders.

¹H NMR(base free; 200 MHz, CDCl₃) δ 1.37–1.44(5H, m), 1.53–1.60(2H, m),1.71–1.78(2H, s), 2.34(3H, s), 2.45(2H, t, J=7.4 Hz), 2.55–2.64(2H, m),2.76–2.93(4H, m), 3.96–4.06(2H, m), 4.67(2H, s), 5.32(1H, br.s),6.78–6.89(2H, m), 6.99(1H, d, J=8.0 Hz), 7.12(2H, d, J=7.2 Hz), 7.54(1H,d, J=1.8 Hz), 7.59(1H, dd, J=8.2, 2.0 Hz). MS m/z: 425 [M+H]⁺

Example 1316-[6-[[2-(3-Ethoxyphenyl)ethyl](methyl)amino]hexanoyl]-2H-1,4-benzoxazin-3(4H)-onehydrochloride

Using 6-(6-bromohexanoyl)-2H-1,4-benzoxazin-3(4H)-one obtained inReference Example 8 and N-[2-(3-ethoxyphenyl)ethyl]-N-methylamineaccording to the same method as that of Example 9, the title compoundwas obtained as colorless amorphous powders.

¹H NMR(base free; 200 MHz, CDCl₃) δ 1.32–1.42(5H, m), 1.49–1.59(2H, m),1.69–1.78(2H, s), 2.30(3H, s), 2.42(2H, t, J=7.6 Hz), 2.59–2.66(2H, m),2.70–2.77(2H, m), 2.89(2H, t, J=7.2 Hz), 3.97–4.04(2H, m), 4.67(2H, s),5.38(1H, br.s), 6.69–6.78(3H, m), 6.98(1H, d, J=8.1 Hz), 7.17(1H, t,J=7.7 Hz), 7.55(1H, d, J=1.8 Hz), 7.58(1H, dd, J=8.4, 2.1 Hz). MS m/z:425 [M+H]⁺

Example 1325-[5-[Methyl(2-phenylethyl)amino]pentanoyl]-1,3-dihydro-2H-benzimidazol-2-onehydrochloride

Using 5-(5-chloropentanoyl)-1,3-dihydro-2H-benzimidazol-2-one obtainedin Reference Example 9 and N-methyl-N-(2-phenylethyl)amine according tothe same method as that of Example 9, the title compound was obtained ascolorless crystals having a melting point of: 240° C.

¹H NMR(300 MHz, DMSO-d₆) δ 1.65–1.75(4H, m), 2.80(3H, d, J=4.8 Hz),3.00–3.08(6H, m), 3.23(2H, m), 7.03(1H, d, J=8.1 Hz), 7.26–7.36(5H, m),7.67(1H, d, J=8.4 Hz), 10.28(1H, s), 10.94(1H, s), 11.09(1H, s).elementary analysis as C₂₁H₂₅N₃O₂.HCl.0.5H₂O calculation value: C,62.69; H, 6.91; N, 10.44. experimental value: C, 62.87; H, 6.63; N,10.37. MS m/z: 352 [M+H]⁺

Example 1335-[5-[[2-(2-Methoxyphenyl)ethyl](methyl)amino]pentanoyl]-1,3-dihydro-2H-benzimidazol-2-onehydrochloride

Using 5-(5-chloropentanoyl)-1,3-dihydro-2H-benzimidazol-2-one obtainedin Reference Example 9 and N-[2-(2-methoxyphenyl)ethyl]-N-methylamineaccording to the same method as that of Example 9, the title compoundwas obtained as colorless crystals having a melting point of 169 to 180°C. (in a sealed tube; dec).

¹H NMR(300 MHz, DMSO-d₆) δ 1.65–1.75(4H, m), 2.80(3H, d, J=4.8 Hz),2.92–3.30(8H, m), 3.81(3H, s), 6.89–6.95(1H, m), 7.00–7.04(2H, m),7.21–7.30(2H, m), 7.50(1H, s), 7.69(1H, dd, J=8.3, 1.7 Hz), 10.09(1H,br.s), 10.95(1H, s), 11.09(1H, s). MS m/z: 382 [M+H]⁺

Example 134N-(5-{5-[[2-(2-methoxyphenyl)ethyl](methyl)amino]pentanoyl}-2,3-dihydro-1H-inden-2-yl)methanesulfonamidehydrochloride

UsingN-[5-(5-chloropentanoyl)-2,3-dihydro-1H-inden-2-yl)methanesulfonamideobtained in Reference Example 233 andN-[2-(2-methoxyphentyl)ethyl]-N-methylamine according to the same methodas that of Example 9, the title compound was obtained as colorlessamorphous powders.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.52–1.81 (4H, m), 2.33 (3H, s),2.47 (2H, t, J=7.4 Hz), 2.60 (2H, m), 2.78 (2H, m), 2.93 (4H, m), 3.00(3H, s), 3.35 (2H, dd, J=16.4, 7.0 Hz), 3.81 (3H, s), 4.32 (1H, m), 5.08(1H, br), 6.81–6.90 (2H, m), 7.11–7.30 (3H, m), 7.78 (2H, m).

Example 1351,3-Dimethyl-5-[5-[methyl(2-phenylethyl)amino]pentanoyl]-1,3-dihydro-2H-benzimidazol-2-onehydrochloride

Using5-(5-chloropentanoyl)-1,3-dimethyl-1,3-dihydro-2H-benzimidazol-2-oneobtained in Reference Example 10 and N-methyl-N-(2-phenylethyl)amineaccording to the same method as that of Example 9, the title compoundwas obtained as colorless crystals having a melting point of 142 to 157°C. (in a sealed tube; dec).

¹H NMR(free base; 300 MHz, CDCl₃) δ 1.54–1.69(2H, m), 1.73–1.83(2H, m),2.31(3H, s), 2.44–2.49(2H, m), 2.58–2.64(2H, m), 2.75–2.80(2H, m),2.98–3.03(2H, m), 3.46(3H, s), 3.47(3H, s), 6.99(1H, d, J=8.1 Hz),7.15–7.30(5H, m), 7.63(1H, d, J=1.5 Hz), 7.69(1H, dd, J=8.3, 1.7 Hz). MSm/z: 380 [M+H]⁺

Example 1365-[5-[(2-Methoxyphenyl)ethyl](methyl)amino]pentanoyl]-1,3-dimethyl-1,3-dihydro-2H-benzimidazol-2-onehydrochloride

Using5-(5-chloropentanoyl)-1,3-dimethyl-1,3-dihydro-2H-benzimidazol-2-oneobtained in Reference Example 10 andN-[2-(2-methoxyphenyl)ethyl]-N-methylamine according to the same methodas that of Example 9, the title compound was obtained as colorlesscrystals having a melting point of 125 to 140° C. (in a sealed tube;dec).

¹H NMR(free base; 200 MHz, CDCl₃) δ 1.65–1.84(4H, m), 2.39(3H, s),2.51–2.69(4H, m), 2.77–2.87(2H, m), 2.99–3.06(2H, m), 3.46(3H, s),3.47(3H, s), 3.82(3H, s), 6.82–6.91(2H, m), 6.99(1H, d, J=8.0 Hz),7.14–7.23(2H, m), 7.63(1H, d, J=1.6 Hz), 7.69(1H, dd, J=8.4, 1.4 Hz). MSm/z: 410 [M+H]⁺

Example 137N-[5-(5-{[2-(2-chlorophenyl)ethyl]amino}pentanoyl)-2,3-dihydro-1H-inden-2-yl]methanesulfonamidehydrochloride

UsingN-[5-(5-chloropentanoyl)-2,3-dihydro-1H-inden-2-yl]methanesulfonamideobtained in Reference Example 233 and 2-(2-chlorophenyl)ethylamineaccording to the same methods as those of Reference Example 19 andExample 1, the title compound was obtained as colorless crystals havinga melting point of 156 to 158° C.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.52–1.81 (4H, m), 2.47 (2H, t,J=7.4 Hz), 2.60 (2H, m), 2.64–2.98 (6H, m), 3.01 (3H, s), 3.35 (2H, dd,J=16.4, 7.2 Hz), 4.30 (1H, m), 5.08 (2H, br), 7.07–7.34 (5H, m), 7.78(2H, m).

Example 1385-[5-[(2-Phenylethyl)amino]pentanoyl]-1,3-dihydro-2H-benzimidazol-2-onehydrochloride

Using 5-(5-chloropentanoyl)-1,3-dihydro-2H-benzimidazol-2-one obtainedin Reference 9 and 2-phenylethylamine according to the same methods asthose of Reference Example 19 and Example 1, the title compound wasobtained as colorless crystals having a melting point of 259° C. (in asealed tube).

¹H NMR(300 MHz, DMSO-d₆) δ 1.68(4H, m), 2.93–3.13(8H, m), 7.03(1H, d,J=7.8 Hz), 7.26–7.37(5H, m), 7.50(1H, s), 7.70(1H, d, J=8.1 Hz),8.88(2H, br.s), 10.95(1H, s), 11.10(1H, s). elementary analysis asC₂₁H₂₅N₃O₃.HCl calculation value: C, 62.45; H, 6.49; N, 10.40.experimental value: C, 62.20; H, 6.42; N, 10.38. MS m/z: 368 [M+H]⁺

Example 1395-(5-[[2-(2-Methoxyphenyl)ethyl]amino]pentanoyl)-1,3-dihydro-2H-benzimidazol-2-onehydrochloride

Using 5-(5-chloropentanoyl)-1,3-dihydro-2H-benzimidazol-2-one obtainedin Reference 9 and 2-(2-methoxyphenyl)ethylamine according to the samemethods as those of Reference Example 19 and Example 1, the titlecompound was obtained as colorless crystals having a melting point of213° C. (in a sealed tube).

¹H NMR(300 MHz, DMSO-d₆) δ 1.67(4H, m), 2.94–3.04(8H, m), 3.80(3H, s),6.89–6.94(1H, m), 6.99–7.04(2H, m), 7.17–7.29(2H, m), 7.50(1H, s),7.69(1H, dd, J=8.1, 1.5 Hz), 8.86(2H, br.s), 10.95(1H, s), 11.10(1H, s).elementary analysis as C₂₀H₂₂N₃O₂Cl.HCl calculation value: C, 58.83; H,5.68; N, 10.29. experimental value: C, 58.51; H, 5.53; N, 10.26. MS m/z:372 [M+H]⁺

Example 1405-(5-[[2-(2-Chlorophenyl)ethyl]amino]pentanoyl)-1,3-dihydro-2H-benzimidazol-2-onehydrochloride

Using 5-(5-chloropentanoyl)-1,3-dihydro-2H-benzoimidazol-2-one obtainedin Reference Example 9 and 2-(2-chlorophenyl)ethylamine according to thesame methods as those of Reference Example 19 and Example 1, the titlecompound was obtained as colorless crystals having a melting point of233° C.

¹H NMR(300 MHz, DMSO-d₆) δ 1.68(4H, m), 2.99–3.11(8H, m), 7.03(1H, d,J=8.1 Hz), 7.31–7.48(5H, m), 7.69(1H, dd, J=8.3, 1.6 Hz), 8.99(2H,br.s), 10.95(1H, s), 11.14(1H, s). elementary analysis asC₂₀H₂₂N₃O₂Cl.HCl calculation value: C, 58.83; H, 5.68; N, 10.29.experimental value: C, 58.51; H, 5.53; N, 10.26. MS m/z: 372 [M+H]⁺

Example 1411,3-Dimethyl-5-[5-[(2-phenylethyl)amino]pentanoyl]-1,3-dihydro-2H-benzimidazol-2-onehydrochloride

Using tert-butyl5-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-5-oxopentyl(2-phenylethyl)carbamateobtained in Reference Example 58 according to the same method,as that ofExample 1, the title compound was obtained as colorless crystals havinga melting point of 187 to 189° C. (in a sealed tube).

¹H NMR(300 MHz, DMSO-d₆) δ 1.71(4H, m), 2.95–3.00(4H, m), 3.11(4H, m),3.36(3H, s), 3.38(3H, s), 7.26–7.38(6H, m), 7.74(1H, d, J=1.2 Hz),7.82(1H, dd , J=8.1, 1.5 Hz), 9.03(2H, br.s). elementary analysis asC₂₂H₂₇N₃O₂.HCl calculation value: C, 65.74; H, 7.02; N, 10.45.experimental value: C, 65.38; H, 7.07; N, 10.55. MS m/z: 366 [M+H]⁺

Example 1425-(5-[[2-(2-Methoxyphenyl)ethyl]amino]pentanoyl)-1,3-dimethyl-1,3-dihydro-2H-benzimidazol-2-onehydrochloride

Using tert-butyl5-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-5-oxopentyl[2-(2-methoxyphenyl)ethyl]carbamateobtained in Reference Example 59 according to the same method as that ofExample 1, the title compound was obtained as colorless crystals havinga melting point of 178° C. (in a sealed tube).

¹H NMR(300 MHz, DMSO-d₆) δ 1.70(4H, m), 2.91–3.13(8H, m), 3.36(3H, s),3.38(3H,s),3.80(3H, s), 6.89–6.94(1H, m), 6.99–7.02(1H, s),7.17–7.20(1H, m), 7.23–7.29(2H, m), 7.74(1H, d, J=1.2 Hz), 7.82(1H, dd,J=8.1, 1.5 Hz), 8.92(2H, br.s). elementary analysis as C₂₃H₂₉N₃O₃.HClcalculation value: C, 63.95; H, 7.00; N, 9.73. experimental value: C,63.72; H, 6.95; N, 9.75. MS m/z: 396 [M+H]⁺

Example 1435-(5-[[2-(2-Chlorophenyl)ethyl]amino]pentanoyl)-1,3-dimethyl-1,3-dihydro-2H-benzimidazol-2-onehydrochloride

Using tert-butyl2-(2-chlorophenyl)ethyl[5-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-5-oxopentyl]carbamateobtained in Reference Example 60 according to the same method as that ofExample 1, the title compound was obtained as colorless crystals havinga melting point of 168 to 169° C.

¹H NMR(300 MHz, DMSO-d₆) δ 1.71(4H, m), 3.01–3.11(8H, m), 3.36(3H, s),3.38(3H,s), 7.26–7.49(5H, m), 7.74(1H, d, J=1.2 Hz), 7.82(1H, dd, J=8.1,1.5 Hz), 9.03 (2H, br.s). elementary analysis as C₂₂H₂₆N₃O₂Cl.HClcalculation value: C, 60.55; H, 6.24; N, 9.62. experimental value: C,60.33; H, 6.25; N, 9.62. MS m/z: 400 [M+H]⁺

Example 1441-(1-Benzyl-2,3-dihydro-1H-indol-5-yl)-5-[[2-(2-methoxyphenyl)ethyl]amino]-1-pentanonedihydrochloride

Using tert-butyl5-(1-benzyl-2,3-dihydro-1H-indol-5-yl)-5-oxopentyl[2-(2-methoxyphenyl)ethyl]carbamate(280 mg) obtained in Reference Example 61 according to the same methodas that of Example 1, the title compound (212 mg) was obtained ascolorless crystals having a melting point of 88 to 89° C.

¹H NMR(400 MHz, DMSO-d₆) δ 1.61–1.65(4H, m), 2.85–3.00(10H, m), 3.47(2H,t, J=8.5 Hz), 3.78(3H, s), 4.43(2H, s), 6.57(1H, d, J=8.3 Hz), 6.89(1H,t, J=8.3 Hz), 6.98(1H, d, J=8.0 Hz), 7.17(1H, d, J=7.5 Hz),7.22–7.35(6H, m), 7.58(1H, br), 7.61(1H, s), 7.70(1H, d, J=8.3 Hz),9.09(2H, s). IR (KBr) νcm⁻¹: 3336, 2950, 2786, 1687, 1602, 1496, 1454,1246, 753.

Example 1451-(1-Benzoyl-2,3-dihydro-1H-indol-5-yl)-5-[[2-(2-methoxyphenyl)ethyl]amino]-1-pentanonehydrochloride

Using tert-butyl5-(1-benzoyl-2,3-dihydro-1H-indol-5-yl)-5-oxopentyl[2-(2-methoxyphenyl)ethyl]carbamateobtained in Reference Example 62 according to the same method as that ofExample 1, the title compound was obtained as colorless crystals havinga melting point of 151 to 152° C.

¹H NMR(400 MHz, DMSO-d₆) δ 1.61–1.71(4H, m), 2.98–3.03(8H, m), 3.18(2H,t, J=8.0 Hz), 3.79(3H, s) 4.05(2H, t, J=8.3 Hz), 6.89(1H, t, J=7.5 Hz),6.98(1H, d, J=7.5 Hz), 7.17(1H, d, J=7.5 Hz), 7.24(1H, t, J=7.5 Hz),7.47–7.60(6H, m), 7.85(1H, d, J=6.6 Hz), 7.87(1H, s), 9.19(2H, s). IR(KBr) νcm⁻¹: 3336, 2948, 2781, 1680, 1644, 1602, 1495, 1440, 1386, 1334,1254, 762.

Example 1465-(5-[[2-(2-Methoxypheny)ethyl]amino]pentanoyl)-N-phenyl-1-indolinecarboxamidehydrochloride

Using tert-butyl5-[1-(anilinocarbonyl)-2,3-dihydro-1H-indol-5-yl]-5-oxopentyl[2-(2-methoxyphenyl)ethyl]carbamateobtained in Reference Example 63 according to the same method as that ofExample 1, the title compound was obtained as colorless crystals havinga melting point of 205 to 206° C. (dec).

¹H NMR(400 MHz, DMSO-d₆) δ 1.63–1.68(4H, m), 2.93–3.03(8H, m), 3.21(2H,t, J=8.5 Hz), 3.79(3H, s), 4.23(2H, t, J=8.3 Hz), 6.89(1H, t, J=7.5 Hz),6.98(1H, d, J=8.3 Hz), 7.02(1H, t, J=7.5 Hz), 7.17(1H, d, J=7.5 Hz),7.24(1H, t, J=7.5 Hz), 7.29(2H, t, J=6.6 Hz), 7.59(2H, d, J=8.5 Hz),7.79(1H, s), 7.82(1H, d, J=8.5 Hz), 7.93(1H, d, J=8.5 Hz), 8.78(1H, s),9.10(2H,s). IR (KBr) νcm⁻¹: 3400, 2936, 2771, 1680, 1597, 1539, 1491,1445, 1340, 1246, 752.

Example 1478-(5-[2-(4-Methoxyphenyl)ethyl]amino}pentanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using tert-butyl2-(4-methoxyphenyl)ethyl[5-oxo-5-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)pentyl]carbamate(1.23 g) obtained in Reference Example 79 according to the same methodas that of Example 1, the title compound was obtained as colorlesscrystals (914 mg) having a melting point of 179 to 181° C.

¹H NMR (200 MHz, DMSO-d₆) δ 1.55–1.80 (4H, m), 2.59 (2H, t, J=7.8 Hz),2.85–3.15 (10H, m), 3.17 (2H, t, J=8.4 Hz), 3.73 (3H, s), 3.99 (2H, t,J=8.4 Hz), 6.89 (2H, d, J=8.4 Hz), 7.18 (2H, d, J=8.4 Hz), 7.73 (2H, s),9.00–9.20 (2H, br). elementary analysis as C₂₅H₃₀N₂O₃.HCl.0.5H₂Ocalculation value: C, 66.43; H, 7.14; N, 6.20. experimental value: C,66.41; H, 7.04; N, 6.06.

Example 1488-(5-{[2-(4-Chlorophenyl)ethyl]amino}pentanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using tert-butyl2-(4-chlorophenyl)ethyl[5-oxo-5-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)pentyl]carbamate(941 mg) obtained in Reference Example 80 according to the same methodas that of Example 1, the title compound was obtained as colorlesscrystals (708 mg) having a melting point of 193 to 195° C.

¹H NMR (200 MHz, DMSO-d₆) δ 1.55–1.80 (4H, m), 2.59 (2H, t, J=7.8 Hz),2.75–3.25 (10H, m), 3.18 (2H, t, J=8.4 Hz), 3.99 (2H, t, J=8.4 Hz), 7.31(2H, d, J=8.4 Hz), 7.40 (2H, d, J=8.4 Hz), 7.73 (2H, s), 9.05–9.30 (2H,br). elementary analysis as C₂₄H₂₇ClN₂O₂.HCl calculation value: C,64.43; H, 6.31; N, 6.26. experimental value: C, 64.07; H, 6.40; N, 6.07.

Example 1498-(5-{[2-(3-Chlorophenyl)ethyl]amino}pentanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using tert-butyl2-(3-chlorophenyl)ethyl[5-oxo-5-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)pentyl]carbamate(1.19 g) obtained in Reference Example 81 according to the same methodas that of Example 1, the title compound was obtained as colorlesscrystals (972 mg) having a melting point of 157 to 159° C.

¹H NMR (200 MHz, DMSO-d₆) δ 1.55–1.80 (4H, m), 2.60 (2H, t, J=7.8 Hz),2.85–3.20 (10H, m), 3.18 (2H, t, J=8.4 Hz), 3.99 (2H, t, J=8.4 Hz),7.20–7.45 (4H, m), 7.73 (2H, s), 8.80–9.05 (2H, br).

Example 1508-(5-{[2-(2-Hydroxyphenyl)ethyl]amino}pentanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using tert-butyl2-(2-hydroxyphenyl)ethyl[5-oxo-5-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)pentyl]carbamate(637 mg) obtained in Reference Example 82 according to the same methodas that of Example 1, the title compound was obtained as colorlesscrystals (530 mg) having a melting point of 112 to 113° C.

¹H NMR (300 MHz, DMSO-d₆) δ 1.60–1.80 (4H, m), 2.59 (2H, t, J=7.8 Hz),2.85–3.10 (10H, m), 3.17 (2H, t, J=8.4 Hz), 3.98 (2H, t, J=8.4 Hz),4.50–5.50 (1H, br), 6.73 (1H, dt, J=7.5, 1.2 Hz), 6.88 (1H, dd, J=7.8,1.2 Hz), 7.00–7.10 (2H, m), 7.72 (1H, s), 7.73 (1H, s), 9.00–9.20 (2H,br). elementary analysis as C₂₄H₂₈N₂O₃.HCl.2.0H₂O calculation value: C,61.99; H, 7.15; N, 6.02. experimental value: C, 61.97; H, 6.87; N, 5.88.

Example 1518-(5-{[2-(2,6-Dichlorophenyl)ethyl]amino}pentanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using tert-butyl2-(2,6-dichlorophenyl)ethyl[5-oxo-5-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)pentyl]carbamate(1.08 g) obtained in Reference Example 83 according to the same methodas that of Example 1, the title compound was obtained as colorlesscrystals (618 mg) having a melting point of 171 to 174° C.

¹H NMR (300 MHz, DMSO-d₆) δ 1.60–1.80 (4H, m), 2.59 (2H, t, J=7.8 Hz),2.90–3.10 (8H, m), 3.17 (2H, t, J=8.4 Hz), 3.25–3.35 (2H, m), 3.98 (2H,t, J=8.4 Hz), 7.33 (1H, dd, J=8.7, 7.5 Hz), 7.49 (2H, d, J=7.5 Hz), 7.72(1H, s), 7.73 (1H, s), 9.25–9.50 (2H, br). elementary analysis asC₂₄H₂₆Cl₂N₂O₂.HCl calculation value: C, 59.82; H, 5.65; N, 5.81.experimental value: C, 59.48; H, 5.67; N, 5.53.

Example 1528-(5-{[2-(2,3-Dimethoxyphenyl)ethyl]amino}pentanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using tert-butyl2-(2,3-dimethoxyphenyl)ethyl[5-oxo-5-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)pentyl]carbamate(1.13 g) obtained in Reference Example 84 according to the same methodas that of Example 1, the title compound was obtained as colorlesscrystals (708 mg) having a melting point of 154 to 156° C.

¹H NMR (300 MHz, DMSO-d₆) δ 1.60–1.80 (4H, m), 2.58 (2H, t, J=7.8 Hz),2.90–3.10 (10H, m), 3.16 (2H, t, J=8.4 Hz), 3.73 (3H, s), 3.78 (3H, s),3.97 (2H, t, J=8.4 Hz), 6.79 (1H, dd, J=8.2, 1.8 Hz), 6.94 (1H, dd,J=8.0, 1.8 Hz), 6.95–7.05 (1H, m), 7.71 (1H, s), 7.72 (1H, s), 8.80–9.10(2H, br). elementary analysis as C₂₆H₃₂N₂O₄.HCl.0.5H₂O calculationvalue: C, 64.79; H, 7.11; N, 5.81. experimental value: C, 64.34; H,7.03; N, 5.55.

Example 1538-(5-[2-(2-Thienyl)ethyl]amino}pentanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using tert-butyl5-oxo-5-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)pentyl[2-(2-thienyl)ethyl]carbamate(1.44 g) obtained in Reference Example 85 according to the same methodas that of Example 1, the title compound was obtained as colorlesscrystals (700 mg) having a melting point of 167 to 169° C.

¹H NMR (300 MHz, DMSO-d₆) δ 1.60–1.80 (4H, m), 2.59 (2H, t, J=7.8 Hz),2.90–3.05 (6H, m), 3.10–3.30 (6H, m), 3.98 (2H, t, J=8.4 Hz), 6.95–7.00(2H, m), 7.40(1H, dd, J=4.8, 1.5 Hz), 7.72 (1H, s), 7.73 (1H, s),9.10–9.30 (2H, br).

Example 1541-(2,3-Dihydro-1,4-benzodioxin-6-yl)-5-{[2-(2-methoxyphenyl)ethyl]amino}-1-pentanonehydrochloride

Using tert-butyl5-(2,3-dihydro-1,4-benzodioxin-6-yl)-5-oxopentyl[2-(2-methoxypenyl)ethyl]carbamate(1.18 g) obtained in Reference Example 86 according to the same methodas that of Example 1, the title compound was obtained as colorlesscrystals (752 mg) having a melting point of 172 to 174° C.

¹H NMR (300 MHz, DMSO-d₆) δ 1.45–1.80 (4H, m), 2.90–3.15 (6H, m),3.30–3.45 (6H, m), 3.80 (3H, s), 6.90 (1H, t, J=7.4 Hz), 6.99 (1H, d,J=8.4 Hz), 7.18 (1H, dd, J=7.4, 1.8 Hz), 7.20–7.30 (2H, m), 7.73 (1H, d,J=1.5 Hz), 7.80 (1H, dd, J=8.1, 1.5 Hz), 8.95–9.15 (2H, br).

Example 1552-Methoxy-5-{5-[(2-phenylethyl)amino]pentanoyl}benzenesulfonamidehydrochloride

Using tert-butyl5-[3-(aminosulfonyl)-4-methoxyphenyl]-5-oxopentyl(2-phenylethyl)carbamate(1.00 g) obtained in Reference Example 87 according to the same methodas that of Example 1, the title compound was obtained as colorlesscrystals (833 mg) having a melting point of 160 to 168° C.

¹H NMR (300 MHz, DMSO-d₆) δ 1.60–1.80 (4H, m), 2.85–3.20 (8H, m), 3.98(3H, s), 7.20–7.40 (8H, m), 8.20 (1H, dd, J=8.8, 2.1 Hz), 8.28 (1H, d,J=2.1 Hz), 8.80–9.10 (2H, br). elementary analysis asC₂₀H₂₆N₂O₄S.HCl.0.5H₂O calculation value: C, 55.10; H, 6.47; N, 6.43..experimental value: C, 55.08; H, 6.37; N, 6.28.

Example 1562-Methoxy-5-(5-{[2-(2-methoxyphenyl)ethyl]amino}pentanoyl)benzenesulfonamidehydrochloride

Using tert-butyl5-[3-(aminosulfonyl)-4-methoxyphenyl]-5-oxopentyl[2-(2-methoxyphenyl)ethyl]carbamate(740 mg) obtained in Reference Example 88 according to the same methodas that of Example 1, the title compound was obtained as colorlesscrystals (504 mg) having a melting point of 139 to 141° C.

¹H NMR (300 MHz, DMSO-d₆) δ 1.60–1.80 (4H, m), 2.85–3.10 (8H, m), 3.78(3H, s), 3.98 (3H, s), 6.89, (1H, dt, J=7.3, 1.5 Hz), 6.98 (1H, d, J=8.1Hz), 7.16 (1H, dd, J=7.3, 1.5 Hz), 7.20–7.25 (3H, m), 7.31 (1H, d, J=8.7Hz), 8.20 (1H, dd, J=8.7, 2.4 Hz), 8.28 (1H, d, J=2.4 Hz), 8.80–9.05(2H, br). elementary analysis as C₂₁H₂₈N₂O₅S.HCl.0.5H₂O calculationvalue: C, 54.13; H, 6.49; N, 6.01. experimental value: C, 54.71; H,6.50; N, 5.86.

Example 1575-(5-{[2-(2-Chlorophenyl)ethyl]amino}pentanoyl)-2-methoxybenzenesulfonamidehydrochloride

Using tert-butyl5-[3-(aminosulfonyl)-4-methoxyphenyl]-5-oxopentyl[2-(2-chlorophenyl)ethyl]carbamate(1.00 g) obtained in Reference Example 89 according to the same methodas that of Example 1, the title compound was obtained as colorlesscrystals (845 mg) having a melting point of 161 to 163° C.

¹H NMR (300 MHz, DMSO-d₆) δ 1.60–1.80 (4H, m), 2.90–3.20 (8H, m), 3.99(3H, s), 7.20–7.50 (7H, m), 8.21 .(1H, dd, J=8.6, 2.1 Hz), 8.30 (1H, d,J=2.1 Hz), 9.00–9.20 (2H, br). elementary analysis as C₂₀H₂₅ClN₂O₄S.HClcalculation value: C, 52.06; H, 5.68; N, 6.07. experimental value: C,52.04; H, 5.72; N, 5.93.

Example 1585-{5-[[2-(2-Chlorophenyl)ethyl](methyl)amino]pentanoyl}-2-methoxybenzenesulfonamidehydrochloride

Using 5-(5-chloropentanoyl)-2-methoxybenzenesulfonamide (800 mg)obtained in Reference Example 66 andN-[2-(2-chlorophenyl)ethyl]-N-methylamine (533 mg) according to the samemethod as that of Example 9, the title compound (126 mg) was obtained aspale yellow amorphous powders.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.45–1.80 (4H, m), 2.33 (3H, s),2.40–2.65 (4H, m), 2.80–3.00 (4H, m), 4.10 (3H, s), 4.50–5.50 (2H, br),7.00–7.40(5H, m), 8.10–8.20(1H, m), 8.20–8.30(1H, m).

Example 159N-isopropyl-2-methoxy-5-(5-{[2-(2-methoxyphenyl)ethyl]amino}pentanoyl)benzenesulfonamidehydrochloride

Using tert-butyl5-{3-[(isopropylamino)sulfonyl]-4-methoxyphenyl}-5-oxopentyl[2-(2-methoxyphenyl)ethyl]carbamate(1.36 g) obtained in Reference Example 90 according to the same methodas that of Example 1, the title compound was obtained as colorlesscrystals (601 mg) having a melting point of 164 to 166° C.

¹H NMR (200 MHz, DMSO-d6) δ 0.96 (6H, d, J=6.6 Hz), 1.60–1.80 (4H, m),2.85–3.40 (9H, m), 3.80 (3H, s), 4.01 (3H, s), 6.85–7.05 (2H, m),7.15–7.45 (4H, m), 8.25 (1H, dd, J=8.4, 2.2 Hz), 8.31 (1H, d, J=2.2 Hz),8.90–9.10 (2H, br). elementary analysis as C₂₄H₃₄N₂O₅S.HCl calculationvalue: C, 57.76; H, 7.07; N, 5.61. experimental value: C, 57.41; H,7.21; N, 5.51.

Example 1605-(5-{[2-(2-Chlorophenyl)ethyl]amino}pentanoyl)-N-isopropyl-2-methoxybenzenesulfonamidehydrochloride

Using tert-butyl2-(2-chlorophenyl)ethyl(5-{3-[(isopropylamino)sulfonyl]-4-methoxyphenyl}-5-oxopentyl)carbamate(1.28 g) obtained in Reference Example 91 according to the same methodas that of Example 1, the title compound was obtained as colorlesscrystals (1.00 g) having a melting point of 179 to 181° C.

¹H NMR (200 MHz, DMSO-d₆) δ 0.96 (6H, d, J=6.6 Hz), 1.60–1.80 (4H, m),2.90–3.50 (9H, m), 4.01 (3H, s), 7.25–7.50 (6H, m), 8.25 (1H, dd, J=8.4,2.2 Hz), 8.32 (1H, d, J=2.2 Hz), 9.00–9.25 (2H, br). elementary analysisas C₂₃H₃₁ClN₂O₄S.HCl calculation value: C, 54.87; H, 6.41; N, 5.56.experimental value: C, 54.67; H, 6.33; N, 5.33.

Example 1615-{5-[[2-(2-Chlorophenyl)ethyl](methyl)amino]pentanoyl}-N-isopropyl-2-methoxybenzenesulfonamidehydrochloride

Using 5-(5-chloropentanoyl)-N-isopropyl-2-methoxybenzenesulfonamide (800mg) obtained in Reference Example 67 andN-[2-(2-chlorophenyl)ethyl]-N-methylamine (470 mg) according to the samemethod as that of Example 9, the title compound (536 mg) was obtained aspale yellow amorphous powders.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.06 (6H, d, J=6.6 Hz), 1.50–1.80(4H, m), 2.34 (3H, s), 2.48 (2H, t, J=7.2 Hz), 2.55–2.70 (2H, m),2.85–2.90 (2H, m), 2.98 (2H, t, J=7.2 Hz), 3.30–3.55 (1H, m), 4.07 (3H,s), 4.85–4.95 (1H, m), 7.05–7.35 (5H, m), 8.19 (1H, dd, J=8.8, 2.2 Hz),8.50 (1H, d, J=2.2 Hz). elementary analysis as C₂₄H₃₃ClN₂O₄S.HCl.0.5H₂Ocalculation value: C, 54.75; H, 6.70; N, 5.32. experimental value: C,54.45; H, 6.94; N, 5.11.

Example 1625-(5-{[2-(2-Methoxyphenyl)ethyl]amino}pentanoyl)-2,3-dihydro-1-benzofuran-7-sulfonamidehydrochloride

Using tert-butyl5-[7-(aminosulfonyl)-2,3-dihydro-1-benzofuran-5-yl]-5-oxopentyl[2-(2-methoxyphenyl)ethyl]carbamate(990 mg) obtained in Reference Example 92 according to the same methodas that of Example 1, the title compound (781 mg) was obtained as paleyellow amorphous powders.

¹H NMR (200 MHz, DMSO-d₆) δ 1.50–1.90 (4H, m), 2.95–3.25 (8H, m), 3.41(2H, t, J=8.6 Hz), 3.89 (3H, s), 4.91 (2H, t, J=8.6 Hz), 6.90–7.10 (2H,m), 7.20–7.40 (2H, m), 7.50 (2H, s), 8.71 (1H, s), 8.20 (1H, s),8.95–9.25 (2H, br). elementary analysis as C₂₂H₂₈N₂O₅S.HCl.0.5H₂Ocalculation value: C, 55.28; H, 6.33; N, 5.86. experimental value: C,55.48; H, 6.50; N, 5.61.

Example 1635-(5-{[2-(2-Chlorophenyl)ethyl]amino}pentanoyl)-2,3-dihydro-1-benzofuran-7-sulfonamidehydrochloride

Using tert-butyl5-[7-(aminosulfonyl)-2,3-dihydro-1-benzofuran-5-yl]-5-oxopentyl[2-(2-chlorophenyl)ethyl]carbamate(900 mg) obtained in Reference Example 93 according to the same methodas that of Example 1, the title compound was obtained as colorlesscrystals (743 mg) having a melting point of 160 to 170° C.

¹H NMR (200 MHz, DMSO-d₆) δ 1.60–1.80 (4H, m), 2.85–3.20 (8H, m), 3.32(2H, t, J=8.6 Hz), 4.82 (2H, t, J=8.6 Hz), 7.25–7.55 (6H, m), 8.11 (1H,s), 8.12 (1H, s), 9.10–9.40 (2H, br). elementary analysis asC₂₁H₂₅ClN₂O₄S.HCl.0.2H₂O calculation value: C, 52.88; H, 5.58; N, 5.87.experimental value: C, 52.93; H, 5.42; N, 5.66.

Example 1645-{5-[[2-(2-Methoxyphenyl)ethyl](methyl)amino]pentanoyl}-2,3-dihydro-1-benzofuran-7-sulfonamidehydrochloride

Using 5-(5-chloropentanoyl)-2,3-dihydro-1-benzofuran-7-sulfonamide (1.00g) obtained in Reference Example 70 andN-[2-(2-methoxyphenyl)ethyl]-N-methylamine (625 mg) according to thesame method as that of Example 9, the title compound (527 mg) wasobtained as pale yellow amorphous powders.

¹H NMR (free base; 300 MHz, CDCl₃) δ 1.50–1.80 (4H, m), 2.36 (3H, s),2.52 (2H, t, J=7.2 Hz), 2.60–2.65 (2H, m), 2.75–2.80 (2H, m), 2.91 (2H,t, J=7.2 Hz), 3.00–5.00 (2H, br), 3.04 (2H, t, J=8.7 Hz), 3.81 (3H, s),4.87 (2H, t, J=8.7 Hz), 6.80–6.90 (2H, m), 7.10–7.20 (2H, m), 7.98 (1H,s), 8.19 (1H, s). elementary analysis as C₂₃H₃₀N₂O₅S.HCl.0.5H₂Ocalculation value: C, 56.14; H, 6.56; N, 5.69. experimental value: C,55.83; H, 6.81; N, 5.45.

Example 1655-{5-[[2-(2-Chlorophenyl)ethyl](methyl)amino]pentanoyl}-2,3-dihydro-1-benzofuran-7-sulfonamidehydrochloride

Using 5-(5-chloropentanoyl)-2,3-dihydro-1-benzofuran-7-sulfonamide (800mg) obtained in Reference Example 70 andN-[2-(2-chlorophenyl)ethyl]-N-methylamine (513 mg) according to the samemethod as that of Example 9, the title compound (519 mg) was obtained aspale yellow amorphous powders.

¹H NMR (free base; 300 MHz, CDCl₃) δ 1.45–1.80 (4H, m), 2.34 (3H, s),2.48 (2H, t, J=7.2 Hz), 2.55–2.65 (2H, m), 2.80–2.90 (4H, m), 3.32 (2H,t, J=8.7 Hz), 3.50–5.50 (2H, br), 4.88 (2H, t, J=8.7 Hz), 7.10–7.35 (4H,m), 7.99 (1H, s), 8.18 (1H, s).

Example 166N-isopropyl-5-(5-{[2-(2-methoxyphenyl)ethyl]amino}pentanoyl)-2,3-dihydro-1-benzofuran-7-sulfonamidehydrochloride

Using tert-butyl5-{7-[(isopropylamino)sulfonyl]-2,3-dihydro-1-benzofuran-5-yl}-5-oxopentyl[2-(2-methoxyphenyl)ethyl]carbamate(1.00 g) obtained in Reference Example 94 according to the same methodas that of Example 1, the title compound was obtained as colorlesscrystals (707 mg) having a melting point of 157 to 159° C.

¹H NMR (200 MHz, DMSO-d₆) δ 0.99 (6H, d, J=6.6 Hz), 1.60–1.85 (4H, m),2.80–3.15 (7H, m), 3.20–3.50 (4H, m), 3.80 (3H, s), 4.82 (2H, t, J=8.8Hz), 6.85–7.05 (2H, m), 7.15–7.30 (2H, m), 7.60 (1H, d, J=7.6 Hz), 8.10(2H, s), 8.90–9.15 (2H, br). elementary analysis as C₂₅H₃₄N₂O₅S.HClcalculation value: C, 58.75; H, 6.90; N, 5.48. experimental value: C,58.33; H, 6.92; N, 5.31.

Example 1675-(5-{[2-(2-Chlorophenyl)ethyl]amino}pentanoyl)-N-isopropyl-2,3-dihydro-1-benzofuran-7-sulfonamidehydrochloride

Using tert-butyl2-(2-chlorophenyl)ethyl(5-{7-[(isopropylamino)sulfonyl]-2,3-dihydro-1-benzofuran-5-yl}-5-oxopentyl)carbamate(2.10 g) obtained in Reference Example 95 according to the same methodas that of Example 1, the title compound was obtained as colorlesscrystals (2.16 g) having a melting point of 149 to 151° C.

¹H NMR (200 MHz, DMSO-d₆) δ 0.99 (6H, d, J=6.6 Hz), 1.60–1.85 (4H, m),2.90–3.20 (7H, m), 3.25–3.45 (4H, m), 4.82 (2H, t, J=8.8 Hz), 7.30–7.50(4H, m), 7.60 (1H, d, J=7.6 Hz), 8.10 (2H, s), 8.90–9.30 (2H, br).elementary analysis as C₂₄H₃₁ClN₂O₄S.HCl calculation value: C, 55.92; H,6.26; N, 5.43. experimental value: C, 55.78; H, 5.99; N, 5.26.

Example 168N-isopropyl-5-{5-[[2-(2-methoxyphenyl)ethyl](methyl)amino]pentanoyl}-2,3-dihydro-1-benzofuran-7-sulfonamidehydrochloride

Using5-(5-chloropentanoyl)-N-isopropyl-2,3-dihydro-1-benzofuran-7-sulfonamide(1.00 g) obtained in Reference Example 71 andN-[2-(2-methoxyphenyl)ethyl]-N-methylamine (551 mg) according to thesame method as that of Example 9, the title compound (470 mg) wasobtained as pale yellow amorphous powders.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.10 (6H, d, J=6.6 Hz), 1.45–1.80(4H, m), 2.32 (3H, s), 2.46 (2H, t, J=7.2 Hz), 2.50–2.60 (2H, m),2.70–2.85 (2H, m), 2.96 (2H, t, J=7.2 Hz), 3.33 (2H, t, J=8.8 Hz),3.35–3.55 (1H, m), 3.82 (3H, s), 4.65–4.80 (1H, m), 4.86 (2H, t, J=8.8Hz), 6.80–6.90 (2H, m), 7.10–7.20 (2H, m), 8.04 (1H, d, J=2.0 Hz), 8.24(1H, d, J=2.0 Hz). elementary analysis as C₂₆H₃₆N₂O₅S.HCl.0.5H₂Ocalculation value: C, 58.47; H, 7.17; N, 5.24. experimental value: C,58.53; H, 7.31; N, 5.15.

Example 1695-{5-[[2-(2-Chlorophenyl)ethyl](methyl)amino]pentanoyl}-N-isopropyl-2,3-dihydro-1-benzofuran-7-sulfonamidehydrochloride

Using5-(5-chloropentanoyl)-N-isopropyl-2,3-dihydro-1-benzofuran-7-sulfonamide(1.00 g) obtained in Reference Example 71 andN-[2-(2-chlorophenyl)ethoxy]-N-methylamine (565 mg) according to thesame method as that of Example 9, the title compound (490 mg) wasobtained as pale yellow amorphous powders.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.10 (6H, d, J=6.6 Hz), 1.45–1.80(4H, m), 2.31 (3H, s), 2.48 (2H, t, J=7.2 Hz), 2.55–2.70 (2H, m),2.80–3.00 (4H, m), 3.33 (2H, t, J=8.8 Hz), 3.35–3.60 (1H, m), 4.68 (1H,d, J=7.4 Hz), 4.86 (2H, t, J=8.8 Hz), 7.10–7.40 (4H, m), 8.04 (1H, d,J=2.0 Hz), 8.24 (1H, d, J=2.0 Hz). elementary analysis asC₂₅H₃₃ClN₂O₄S.HCl.0.5H₂O calculation value: C, 55.76; H, 6.55; N, 5.20.experimental value: C, 55.38; H, 6.72; N, 5.07.

Example 1706-(6-{[2-(2-Chlorophenyl)ethyl]amino}pentanoyl)-2,2-dimethyl-8-chlomansulfonamidehydrochloride

Using tert-butyl5-[8-(aminosulfonyl)-2,2-dimethyl-3,4-dihydro-2H-chlomen-6-yl]-5-oxopentyl[2-(2-chlophenyl)ethyl]carbamate(715 mg) obtained in Reference Example 96 according to the same methodas that of Example 1, the title compound (568 mg) was obtained ascolorless amorphous powders.

¹H NMR (300 MHz, DMSO-d₆) δ 1.40 (6H, s), 1.60–1.80 (4H, m), 1.87 (2H,t, J=6.6 Hz), 2.88 (2H, t, J=6.6 Hz), 2.90–3.20 (8H, m), 7.01 (2H, s),7.25–7.50 (4H, m), 7.39 (1H, d, J=2.1 Hz), 8.14 (1H, d, J=2.1 Hz),9.10–9.30 (2H, br). elementary analysis as C₂₄H₃₁ClN₂O₄S.HCl.0.5H₂Ocalculation value: C, 54.96; H, 6.34; N, 5.34. experimental value: C,55.00; H, 6.36; N, 5.11.

Example 1717-{5-[(2-Phenylethyl)amino]pentanoyl}-2,3-dihydro-1,4-benzodioxin-5-sulfonamidehydrochloride

Using tert-butyl5-[8-(aminosulfonyl)-2,3-dihydro-1,4-benzodioxin-6-yl]-5-oxopentyl(2-phenylethyl)carbamate(1.05 g) obtained in Reference Example 97 according to the same methodas that of Example 1, the title compound was obtained as colorlesscrystals (832 mg) having a melting point of 152 to 154° C.

¹H NMR (300 MHz, DMSO-d₆) δ 1.55–1.80 (4H, m), 2.85–3.20 (8H, m),4.30–4.40 (2H, m), 4.40–4.50 (2H, m), 7.20–7.40 (7H, m), 7.69 (1H, d,J=2.1 Hz), 7.89 (1H, d, J=2.1 Hz), 8.95–9.20 (2H, br). elementaryanalysis as C₂₁H₂₆N₂O₅S.HCl calculation value: C, 55.32; H, 6.19; N,6.14. experimental value: C, 55.15; H, 6.06; N, 6.00.

Example 1727-(5-{[2-(2-Methoxyphenyl)ethyl]amino}pentanoyl)-2,3-dihydro-1,4-benzodioxin-5-sulfonamidehydrochloride

Using tert-butyl5-[8-(aminosulfonyl)-2,3-dihydro-1,4-benzodioxin-6-yl]-5-oxopentyl[2-(2-methoxyphenyl)ethyl]carbamate(820 mg) obtained in Reference Example 98 according to the same methodas that of Example 1, the title compound was obtained as colorlesscrystals (632 mg) having a melting point of 166 to 168° C.

¹H NMR (300 MHz, DMSO-d₆) δ 1.55–1.80 (4H, m), 2.85–3.10 (8H, m), 3.80(3H, s), 4.30–4.40 (2H, m), 4.40–4.50 (2H, m), 6.90 (1H, t, J=7.5 Hz),6.99 (1H, d, J=8.1 Hz), 7.17 (1H, d, J=7.5 Hz), 7.25 (1H, t, J=7.5 Hz),7.36 (2H, s), 7.69 (1H, d, J=2.1 Hz), 7.88 (1H, d, J=2.1 Hz), 8.80–9.15(2H, br). elementary analysis as C₂₂H₂₈N₂O₆S.HCl calculation value: C,54.48; H, 6.03; N, 5.78. experimental value: C, 54.12; H, 6.13; N, 5.64.

Example 1737-(5-{[2-(2-Chlorophenyl)ethyl]amino}pentanoyl)-2,3-dihydro-1,4-benzodioxin-5-sulfonamidehydrochloride

Using tert-butyl5-[8-(aminosulfonyl)-2,3-dihydro-1,4-benzodioxin-6-yl]-5-oxopentyl[2-(2-chlorophenyl)ethyl]carbamate(1.08 g) obtained in Reference Example 99 according to the same methodas that of Example 1, the title compound was obtained as colorlesscrystals (850 mg) having a melting point of 178 to 180° C.

¹H NMR (300 MHz, DMSO-d₆) δ 1.60–1.80 (4H, m), 2.90–3.20 (8H, m),4.30–4.40 (2H, m), 4.40–4.50 (2H, m), 7.25–7.50 (6H, m), 7.69 (1H, d,J=2.1 Hz), 7.88 (1H, d, J=2.1 Hz), 8.95–9.25 (2H, br). elementaryanalysis as C₂₁H₂₅ClN₂O₅S.HCl.H₂O calculation value: C, 49.71; H, 5.56;N, 5.52. experimental value: C, 49.72; H, 5.61; N, 5.35.

Example 1747-{5-[[2-(2-Chlorophenyl)ethyl](methyl)amino]pentanoyl}-2,3-dihydro-1,4-benzodioxin-5-sulfonamidehydrochloride

Using 5-chloro-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-pentanone (1.00 g)obtained in Reference Example 75 andN-[2-(2-chlorophenyl)ethyl]-N-methylamine (565 mg) according to the samemethod as that of Example 9, the title compound (490 mg) was obtained aspale yellow amorphous powders.

¹H NMR (free base; 300 MHz, CDCl₃) δ 1.45–1.75 (4H, m), 2.31 (3H, s),2.45 (2H, t, J=7.2 Hz), 2.50–2.65 (2H, m), 2.80–2.95 (4H, m), 4.00–5.50(2H, br), 4.30–4.40 (2H, m), 4.35–4.40 (2H, m), 7.05–7.35 (4H, m), 7.63(1H, s), 7.98 (1H, s).

Example 175N-(2-methoxy-5-{5-[(2-phenylethyl)amino]pentanoyl}phenyl)methanesulfonamidehydrochloride

Using tert-butyl5-{4-methoxy-3-[(methylsulfonyl)amino]phenyl}-5-oxopentyl(2-phenylethyl)carbamate(1.32 g) obtained in Reference Example 100 according to the same methodas that of Example 1, the title compound was obtained as colorlesscrystals (945 mg) having a melting point of 131 to 133° C.

¹H NMR (300 MHz, DMSO-d₆) δ 1.55–1.75(4H, m), 2.85–3.20(8H, m), 2.96(3H,s), 3.89(3H, s), 7.15–7.40(6H, m), 7.80–7.90(2H, m), 8.85–9.15(2H, br),9.14(1H, s). elementary analysis as C₂₁H₂₈N₂O₄S.HCl.0.5H₂O calculationvalue: C, 56.05; H, 6.72; N, 6.23. experimental value: C, 56.18; H,6.62; N, 6.25.

Example 176N-[2-methoxy-5-(5-{[2-(2-methoxyphenyl)ethyl]amino}pentanoyl)phenyl]methanesulfonamidehydrochloride

Using tert-butyl5-{4-methoxy-3-[(methylsulfonyl)amino]phenyl}-5-oxopentyl[2-(2-methoxyphenyl)ethyl]carbamate(550 mg) obtained in Reference Example 101 according to the same methodas that of Example 1, the title compound was obtained as colorlesscrystals (374 mg) having a melting point of 129 to 131° C.

¹H NMR (300 MHz, DMSO-d₆) δ 1.60–1.75(4H, m), 2.90–3.10(8H, m), 2.98(3H,s), 3.80(3H, s), 3.92(3H, s), 6.91(1H, t, J=7.5 Hz), 7.00(1H, d, J=8.1Hz), 7.15–7.30(3H, m), 7.86(1H, d, J=1.8 Hz), 7.89(1H, dd, J=8.5, 1.8Hz), 8.85–9.05(2H, br), 9.15(1H, s). elementary analysis asC₂₂H₃₀N₂O₅S.HCl.0.5H₂O calculation value: C, 55.05; H, 6.72; N, 5.84.experimental value: C, 55.20; H, 6.44; N, 5.80.

Example 177N-[5-(5-{[2-(2-chlorophenyl)ethyl]amino}pentanoyl)-2-methoxyphenyl]methanesulfonamidehydrochloride

Using tert-butyl2-(2-chlorophenyl)ethyl(5-{4-methoxy-3-[(methylsulfonyl)amino]phenyl}-5-oxopentyl)carbamate(1.52 g) obtained in Reference Example 102 according to the same methodas that of Example 1, the title compound was obtained as colorlesscrystals (1.03 g) having a melting point of 133 to 135° C.

¹H NMR (300 MHz, CDCl₃) δ 1.75–2.10 (4H, m), 2.95–3.15 (4H, m), 3.00(3H, s), 3.20–3.30 (2H, m), 3.35–3.45 (2H, m), 3.96 (3H, s), 6.92 (1H,s), 6.94 (1H, d, J=8.4 Hz), 7.10–7.40 (4H, m), 7.75 (1H, dd, J=5.7, 1.4Hz), 8.04 (1H, d, J=1.4 Hz), 9.65–9.80 (2H, br). elementary analysis asC₂₁H₂₇ClN₂O₄S.HCl.0.5H₂O calculation value: C, 52.07; H, 6.03; N, 5.78.experimental value: C, 52.43; H, 5.78; N, 5.81.

Example 178N-(2-methoxy-5-{6-[(2-phenylethyl)amino]hexanoyl}phenyl)methanesulfonamidehydrochloride

Using tert-butyl6-{4-methoxy-3-[(methylsulfonyl)amino]phenyl}-6-oxohexyl(2-phenylethyl)carbamate(918 mg) obtained in Reference Example 103 according to the same methodas that of Example 1, the title compound was obtained as colorlesscrystals (751 mg) having a melting point of 136 to 138° C.

¹H NMR (300 MHz, DMSO-d₆) δ 1.30–1.45(2H, m), 1.55–1.75(4H, m),2.85–3.10(8H, m), 2.98(3H, s), 3.92(3H, s), 7.15–7.40(6H, m),7.80–7.90(2H, m), 8.95–9.20(2H, br), 9.16(1H, s). elementary analysis asC₂₂H₃₀N₂O₄S.HCl.1.5H₂O calculation value: C, 54.82; H, 7.11; N, 5.81.experimental value: C, 55.19; H, 7.34; N, 5.72.

Example 179N-[2-methoxy-5-(6-{[2-(2-methoxyphenyl)ethyl]amino}hexanoyl)phenyl]methanesulfonamidehydrochloride

Using tert-butyl6-{4-methoxy-3-[(methylsulfonyl)amino]phenyl}-6-oxohexyl[2-(2-methoxyphenyl)ethyl]carbamate(1.00 g) obtained in Reference Example 104 according to the same methodas that of Example 1, the title compound was obtained as colorlesscrystals (802 mg) having a melting point of 142 to 144° C.

¹H NMR (300 MHz, DMSO-d₆) δ 1.30–1.45(2H, m), 1.55–1.75(4H, m),2.80–3.10(8H, m), 2.98(3H, s), 3.80(3H, s), 3.92(3H, s), 6.92(1H, t,J=7.5 Hz), 7.00(1H, d, J=7.5 Hz), 7.15–7.30(3H, m), 7.80–7.90(2H, m),8.75–9.05(2H, br), 9.16(1H, s). elementary analysis as C₂₃H₃₂N₂O₅S.HClcalculation value: C, 56.95; H, 6.86; N, 5.78. experimental value: C,56.61; H, 6.87; N, 5.69.

Example 180N-[5-(6-{[2-(2-Chlorophenyl)ethyl]amino}hexanoyl)-2-methoxyphenyl]methanesulfonamidehydrochloride

Using tert-butyl2-(2-chlorophenyl)ethyl(6-{4-methoxy-3-[(methylsulfonyl)amino]phenyl}-6-oxohexyl)carbamate(1.26 g) obtained in Reference Example 105 according to the same methodas that of Example 1, the title compound was obtained as colorlesscrystals (941 mg) having a melting point of 112 to 115° C.

¹H NMR (300 MHz, DMSO-d₆) δ 1.30–1.45(2H, m), 1.55–1.75(4H, m),2.80–3.00(8H, m), 2.98(3H, s), 3.92(3H, s), 7.19(1H, d, J=8.7 Hz),7.25–7.50(4H, m), 7.80–7.90(2H, m), 8.90–9.20(2H, br), 9.16(1H, s).elementary analysis as C₂₂H₂₉ClN₂O₄S.HCl.0.5H₂O calculation value: C,53.01; H, 6.27; N, 5.62. experimental value: C, 52.96; H, 6.24; N, 5.64.

Example 181 1-(1H-indol-3-yl)-5-[(2-phenylethyl)amino]-1-pentanonehydrochloride

Using tert-butyl 5-(1H-indol-3-yl)-5-oxopentyl(2-phenylethyl)carbamate(1.00 g) obtained in Reference Example 106 according to the same methodas that of Example 1, the title compound was obtained as colorlesscrystals (391 mg) having a melting point of 171 to 173° C.

¹H NMR (200 MHz, DMSO-d₆) δ 1.65–1.80(4H, m), 2.85–3.20(8H, m),7.10–7.40(7H, m), 7.48(1H, d, J=7.2 Hz), 8.20(1H, d, J=7.5 Hz), 8.36(1H,d, J=3.2 Hz), 8.80–9.15(2H, br), 12.12(1H, s).

Example 1821-(1H-indol-3-yl)-5-{[2-(2-methoxyphenyl)ethyl]amino]-1-pentanonehydrochloride

Using tert-butyl5-(1H-indol-3-yl)-5-oxopentyl[2-(2-methoxyphenyl)ethyl]carbamate (901mg) obtained in Reference Example 107 according to the same method asthat of Example 1, the title compound was obtained as colorless crystals(672 mg) having a melting point of 143 to 145° C.

¹H NMR (200 MHz, DMSO-d₆) δ 1.65–1.80(4H, m), 2.85–3.15(8H, m), 3.80(3H,s), 6.91(1H, t, J=7.4 Hz), 6.99(1H, d, J=8.0 Hz), 7.10–7.30(4H, m),7.45–7.55(1H, m), 8.15–8.25(1H, m), 8.37(1H, d, J=3.2 Hz), 8.95–9.20(2H,br), 12.12(1H, s). elementary analysis as C₂₂H₂₆N₂O₂.HCl.2.0H₂Ocalculation value: C, 62.48; H, 7.39; N, 6.62. experimental value: C,62.48; H, 6.95; N, 6.30.

Example 1835-{[2-(2-Chlorophenyl)ethyl]amino}-1-(1H-indol-3-yl)-1-pentanonehydrochloride

Using tert-butyl2-(2-chlorophenyl)ethyl[5-(1H-indol-3-yl)-5-oxopentyl]carbamate (1.00 g)obtained in Reference Example 108 according to the same method as thatof Example 1, the title compound was obtained as colorless crystals (925mg) having a melting point of 149 to 151° C.

¹H NMR (300 MHz, DMSO-d₆) δ 1.65–1.85(4H, m), 2.80–3.20(8H, m),7.05–7.50(7H, m), 8.20(1H, d, J=6.3 Hz), 8.37(1H, d, J=3.0 Hz),9.05–9.30(2H, br), 12.12(1H, s). elementary analysis asC₂₁H₂₃ClN₂O.HCl.3H₂O calculation value: C, 56.63; H, 6.79; N, 6.29.experimental value: C, 56.41; H, 6.17; N, 6.04.

Example 184 1-(1H-indol-3-yl)-6-[(2-phenylethyl)amino]-1-hexanonehydrochloride

Using tert-butyl 6-(1H-indol-3-yl)-6-oxohexyl(2-phenylethyl)carbamate(838 mg) obtained in Reference Example 109 according to the same methodas that of Example 1, the title compound was obtained as colorlesscrystals (650 mg) having a melting point of 160 to 162° C.

¹H NMR (300 MHz, DMSO-d₆) δ 1.30–1.50 (2H, m), 1.55–1.80 (4H, m),2.80–3.20 (8H, m), 7.10–7.35 (7H, m), 7.47 (1H, d, J=7.8 Hz), 8.20 (1H,d, J=6.9 Hz), 8.35–8.40 (1H, m), 8.95–9.20 (2H, br), 12.05 (1H, s).elementary analysis as C₂₂H₂₆N₂O.HCl calculation value: C, 71.24; H,7.34; N, 7.55. experimental value: C, 70.87; H, 7.45; N, 7.53.

Example 1851-(1H-indol-3-yl)-6-{[(2-(2-methoxyphenyl)ethyl)amino}-1-hexanonehydrochloride

Using tert-butyl6-(1H-indol-3-yl)-6-oxohexyl[2-(2-methoxyphenyl)ethyl]carbamate (688 mg)obtained in Reference Example 110 according to the same method as thatof Example 1, the title compound was obtained as colorless crystals (552mg) having a melting point of 171 to 173° C.

¹H NMR (300 MHz, DMSO-d₆) δ 1.30–1.45 (2H, m), 1.55–1.75 (4H, m),2.80–3.10 (8H, m), 3.80 (3H, s), 6.91 (1H, t, J=7.5 Hz), 7.00 (1H, d,J=8.4 Hz), 7.10–7.30 (4H, m), 7.47 (1H, d, J=7.8 Hz), 8.20 (1H, d, J=6.9Hz), 8.35 (1H, d, J=3.0 Hz), 8.85–9.05 (2H, br), 12.04 (1H, s).

Example 1866-{[2-(2-Chlorophenyl)ethyl]amino}-1-(1H-indol-3-yl)-1-hexanonehydrochloride

Using tert-butyl2-(2-chlorophenyl)ethyl[6-(1H-indol-3-yl)-6-oxohexyl]carbamate (860 mg)obtained in Reference Example 111 according to the same method as thatof Example 1, the title compound was obtained as colorless crystals (791mg) having a melting point of 151 to 153° C.

¹H NMR (300 MHz, DMSO-d₆) δ 1.30–1.45(2H, m), 1.55–1.80(4H, m),2.80–3.20(8H, m), 7.15–7.50(7H, m), 8.20(1H, d, J=6.9 Hz), 8.36(1H, d,J=3.0 Hz), 9.10–9.30(2H, br), 12.04(1H, s). elementary analysis asC₂₂H₂₅ClN₂O.HCl.2.5H₂O calculation value: C, 58.67; H, 6.94; N, 6.22.experimental value: C, 58.04; H, 6.56; N, 6.01.

Example 187 5-[(2-Phenylethyl)amino]-1-(2-thienyl)-1-pentanonehydrochloride

Using tert-butyl 5-oxo-5-(2-thienyl)pentyl(2-phenylethyl)carbamate (908mg) obtained in Reference Example 112 according to the same method asthat of Example 1, the title compound was obtained as colorless crystals(908 mg) having a melting point of 161 to 163° C.

¹H NMR (300 MHz, DMSO-d₆) δ 1.60–1.80 (4H, m), 2.85–3.20 (8H, m),7.20–7.40 (6H, m), 7.95–8.05 (2H, m), 9.10–9.35 (2H, br).

Example 1885-{[2-(2-Methoxyphenyl)ethyl]amino}-1-(2-thienyl)-1-pentanonehydrochloride

Using tert-butyl2-(2-methoxyphenyl)ethyl[5-oxo-5-(2-thienyl)pentyl]carbamate (1.45 g)obtained in Reference Example 113 according to the same method as thatof Example 1, the title compound was obtained as colorless crystals(1.04 g) having a melting point of 101 to 103° C.

¹H NMR (300 MHz, DMSO-d₆) δ 1.60–1.80(4H, m), 2.85–3.10(8H, m), 3.80(3H,s), 6.91(1H, t, J=7.2 Hz), 7.00(1H, d, J=8.1 Hz), 7.18(1H, d, J=7.2 Hz),7.20–7.30(2H, m), 7.95–8.05(2H, m), 8.95–9.15(2H, br). elementaryanalysis as C₁₈H₂₃NO₂S.HCl calculation value: C, 61.09; H, 6.84; N,3.96. experimental value: C, 60.73; H, 6.62; N, 3.85.

Example 189 5-{[2-(2-Chlorophenyl)ethyl]amino}-1-(2-thienyl)-1-pentanonehydrochloride

Using tert-butyl2-(2-chrolophenyl)ethyl[5-oxo-5-(2-thienyl)pentyl]carbamate (1.47 g)obtained in Reference Example 114 according to the same method as thatof Example 1, the title compound was obtained as colorless crystals(1.09 g) having a melting point of 146 to 147° C.

¹H NMR (300 MHz, DMSO-d₆) δ 1.60–1.80(4H, m), 2.85–3.20(8H, m),7.20–7.50(5H, m), 7.95–8.05(2H, m), 9.05–9.30(2H, br). elementaryanalysis as C₁₇H₂₀ClNOS.HCl calculation value: C, 56.98; H, 5.91; N,3.91. experimental value: C, 56.76; H, 5.82; N, 3.96.

Example 190 6-[(2-Phenylethyl)amino]-1-(2-thienyl)-1-hexanonehydrochloride

Using tert-butyl 6-oxo-6-(2-thienyl)hexyl(2-phenylethyl)carbamate (863mg) obtained in Reference Example 115 according to the same method asthat of Example 1, the title compound was obtained as colorless crystals(685 mg) having a melting point of 152 to 154° C.

¹H NMR (300 MHz, DMSO-d₆) δ 1.30–1.45(2H, m), 1.55–1.80(4H, m),2.80–3.20(8H, m), 7.20–7.40(6H, m), 7.95–8.05(2H, m), 9.00–9.20(2H, br).

Example 191 6-{[2-(2-Methoxyphenyl)ethyl]amino}-1-(2-thienyl)-1-hexanonehydrochloride

Using tert-butyl2-(2-methoxypheny)ethyl[6-oxo-6-(2-thienyl)hexyl]carbamate (884 mg)obtained in Reference Example 116 according to the same method as thatof Example 1, the title compound was obtained as colorless crystals (643mg) having a melting point of 107 to 109° C.

¹H NMR (300 MHz, DMSO-d₆) δ 1.30–1.45(2H, m), 1.55–1.75(4H, m),2.80–3.10(8H, m), 3.80(3H, s), 6.92(1H, t, J=7.5 Hz), 7.00(1H, d, J=8.4Hz), 7.18(1H, d, J=6.9 Hz), 7.20–7.30(2H, m), 7.95–8.05(2H, m),8.80–9.10(2H, br). elementary analysis as C₁₉H₂₅NO₂S.HCl calculationvalue: C, 62.02; H, 7.12; N, 3.81. experimental value: C, 61.80; H,7.04; N, 3.88.

Example 192 6-{[2-(2-Chlorophenyl)ethyl]amino}-1-(2-thienyl)-1-hexanonehydrochloride

Using tert-butyl2-(2-chloropheny)ethyl[6-oxo-6-(2-thienyl)hexyl]carbamate (1.07 g)obtained in Reference Example 117 according to the same method as thatof Example 1, the title compound was obtained as colorless crystals (849mg) having a melting point of 149 to 151° C.

¹H NMR (300 MHz, DMSO-d₆) δ 1.30–1.45(2H, m), 1.55–1.75(4H, m),2.80–3.20(8H, m), 7.20–7.50(5H, m), 7.95–8.05(2H, m), 9.00–9.35(2H, br).elementary analysis as C₁₈H₂₂ClNOS.HCl.H₂O calculation value: C, 55.38;H, 6.46; N, 3.59. experimental value: C, 55.20; H, 6.57; N, 3.67.

Example 193(±)-8-[5-(1,2,3,4-Tetrahydro-1-naphthalenylamino)pentanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using tert-butyl(±)-5-oxo-5-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)pentyl(1,2,3,4-tetrahydro-1-naphthalenyl)carbamate(520 mg) obtained in Reference Example 118 according to the same methodas that of Example 1, the title compound (420 mg) was obtained as paleyellow amorphous powders

¹H NMR (300 MHz, DMSO-d₆) δ 1.60–2.25(8H, m), 2.59(2H, t, J=7.6 Hz),2.65–3.05(8H, m), 3.17(2H, t, J=8.4 Hz), 3.60–3.70(1H, m), 3.98(2H, t,J=8.4 Hz), 7.15–7.35(3H, m), 7.65–7.80(3H, m), 9.05–9.35(2H, br).

Example 194(±)-8-{5-[(1,2-Diphenylethyl)amino]pentanoyl}-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using tert-butyl(±)-1,2-diphenylethyl[-5-oxo-5-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)pentyl]carbamate(837 mg) obtained in Reference Example 119 according to the same methodas that of Example 1, the title compound was obtained as colorlesscrystals (472 mg) having a melting point of 210 to 212° C.

¹H NMR (300 MHz, DMSO-d₆) δ 1.45–1.80(4H, m), 2.50–2.65(3H, m),2.75–3.05(5H, m), 3.10–3.25(3H, m), 3.55–3.70(1H, m), 3.99(2H, t, J=8.4Hz), 4.40–4.55(1H, m), 6.95–7.05(2H, m), 7.10–7.20(3H, m), 7.30–7.40(3H,m), 7.40–7.50(2H, m), 7.70–7.80(2H, m), 9.45–9.60(1H, br),9.85–10.05(1H, br).

Example 1958-(5-{Benzyl[2-(2-methoxyphenyl)ethyl]amino}pentanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using8-(5-chloropentanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(500 mg) obtained in Reference Example 1 andN-benzyl-N-[2-(2-methoxyphenyl)ethyl]amine (455 mg) according to thesame method as that of Example 9, the title compound (353 mg) wasobtained as pale yellow amorphous powders.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.50–1.90(6H, m), 2.55(2H, t, J=6.8Hz), 2.60–3.30(10H, m), 3.65(2H, s), 3.74(3H, s), 4.10(2H, t, J=8.8 Hz),6.75–6.90(2H, m), 7.05–7.35(7H, m), 7.64(1H, s), 7.68(1H, s).

Example 196Trans-8-[(4-{[(2-phenylethyl)amino]methyl}cyclohexyl)carbonyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

(2-Bromoethyl)benzene (471 mg) was added dropwise to a suspension oftrans-8-{[4-(aminomethyl)cyclohexyl]carbonyl}-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride (1.00 g) obtained in Reference Example 78 and potassiumcarbonate (1.00 g) in dimethylformamide (3 ml) at room temperature Afterstirring at 120° C. for 30 minutes, water (30 ml) and ethyl acetate (30ml) were added to the reaction mixture, and extracted with ethyl acetateThe extract was washed with brine, dried over anhydrous magnesiumsulfate, and the solvent was evaporated under reduced pressure Theresulting residue was purified by silica gel chromatography (elutingsolvent; ethyl acetate methanol (9:1)) to give a free base compound ofthe title compound as a colorless oil (500 mg). Further treatment with ahydrogen chloride-ethyl acetate solution afforded the title compound ascolorless crystals (474 mg) having a melting point of 252 to 254° C.

¹H NMR (free base; 300 MHz, CDCl₃) δ 0.95–1.20 (2H, m), 1.35–1.70 (5H,m), 1.75–2.05 (4H, m), 2.51 (2H, d, J=6.3 Hz), 2.70 (2H, t, J=7.8 Hz),2.75–2.90 (3H, m), 3.01 (2H, t, J=7.8 Hz), 3.05–3.15 (1H, m), 3.22 (2H,t, J=8.4 Hz), 4.12 (2H, t, J=8.4 Hz), 7.10–7.35 (5H, m), 7.64 (1H, s),7.68 (1H, s). elementary analysis as C₂₇H₃₂ClN₂O₂.HCl calculation value:C, 70.19; H, 7.42; N, 6.06. experimental value: C, 70.58; H, 7.35; N,5.81.

Example 197trans-8-{[4-({[2-(2-Chlorophenyl)ethyl]amino}methyl)cyclohexyl]carbonyl}-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Usingtrans-8-{[4-(aminomethyl)cyclohexyl]carbonyl}-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride (758 mg) obtained in Reference Example 78 and2-(2-chlorophenyl)ethyl methanesulfonate (510 mg) according to the samemethod as that of Example 196, the title compound was obtained ascolorless crystals (454 mg) having a melting point of 271 to 2731° C.

¹H NMR (free base; 300 MHz, CDCl₃) δ 0.95–1.20 (2H, m), 1.35–1.70 (5H,m), 1.75–2.05 (4H, m), 2.55 (2H, d, J=6.3 Hz), 2.71 (2H, t, J=7.8 Hz),2.80–2.95 (3H, m), 3.02 (2H, t, J=7.8 Hz), 3.05–3.20 (1H, m), 3.23 (2H,t, J=8.4 Hz), 4.13 (2H, t, J=8.4 Hz), 7.10–7.40 (4H, m), 7.65 (1H, s),7.69 (1H, s). elementary analysis as C₂₇H₃₁N₂O₂Cl.HCl.0.5H₂O calculationvalue: C, 65.32; H, 6.70; N, 5.64. experimental value: C, 65.70; H,6.52; N, 5.54.

Example 1981-(3-Acetyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-5-{[2-(2-chlorophenyl)ethyl]amino}-1-pentanonehydrochloride

Using1-(3-acetyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-5-chloro-1-pentanoneobtained in Reference Example 122 and 2-(2-chlorophenyl)ethylamineaccording to the same methods as those of Example 19 and Example 1, thetitle compound was obtained as colorless crystals having a melting pointof 117 to 119° C.

¹H NMR (300 MHz, DMSO-d₆) δ 1.68 (4H, m), 2.08 (3H, s), 2.91 (4H, m),3.05 (8H, m), 3.56 (4H, m), 7.33–7.46 (5H, m), 7.77 (2H, m), 9.18 (2H,br).

Example 1991-(3-Acetyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-5-{[2-(2-methoxyphenyl)ethyl]amino}-1-pentanonehydrochloride

Using1-(3-acetyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-5-chloro-1-pentanoneobtained in Reference Example 122 and 2-(2-methoxyphenyl)ethylamineaccording to the same methods as those of Example 19 and Example 1, thetitle compound was obtained as colorless crystals having a melting pointof 93 to 94° C.

¹H NMR (300 MHz, DMSO-d₆) δ 1.67 (4H, m), 2.08 (3H, s), 2.93 (4H, m),3.04 (8H, m), 3.58 (4H, m), 3.80 (3H, s), 6.88–7.02 (2H, m), 7.17–7.33(3H, m), 7.75 (2H, m), 8.83 (2H, br).

Example 2005-{[2-(2-Chlorophenyl)ethyl]amino}-1-[3-(methylsulfonyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]-1-pentanonehydrochloride

Using5-chloro-1-[3-(methylsulfonyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]-1-pentanoneobtained in Reference Example 123 and 2-(2-chlorophenyl)ethylamineaccording to the same methods as those of Reference Example 19 andExample 1, the title compound was obtained as colorless crystals havinga melting point of 162 to 164° C.

¹H NMR (300 MHz, DMSO-d₆) δ 1.69 (4H, m), 2.88 (3H, s), 3.10 (8H, m),3.36 (8H, m), 7.33–7.46 (5H, m), 7.78 (2H, m), 8.99 (2H, br).

Example 2015-{[2-(2-Methoxyphenyl)ethyl]amino}-1-[3-(methylsulfonyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]-1-pentanonehydrochloride

Using 5-(5-chloropentanoyl)-2-methoxybenzenesulfonamide obtained inReference Example 66 and N-[2-(2-chlorophenyl)ethyl]-N-methylamineaccording to the same methods as those of Reference Example 19 andExample 1, the title compound was obtained as pale yellow amorphouspowders.

¹H NMR (300 MHz, DMSO-d₆) δ 1.67 (4H, m), 2.88 (3H, s), 2.96–3.07 (10H,m), 3.36 (6H, m), 3.80 (3H, s), 6.88–7.23 (2H, m), 7.17–7.36 (3H, m),7.78 (2H, m), 8.88 (2H, br).

Example 2027-(5-{[2-(2-Chlorophenyl)ethyl]amino}pentanoyl)-N-ethyl-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxamidehydrochloride

Using7-(5-chloropentanoyl)-N-ethyl-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxamideobtained in Reference Example 124 and 2-(2-chlorophenyl)ethylamineaccording to the same methods as those of Reference Example 19 andExample 1, the title compound was obtained as colorless crystals havinga melting point of 149 to 150° C.

¹H NMR (300 MHz, DMSO-d₆) δ 1.02 (3H, t, J=7.0 Hz), 1.69 (4H, m), 2.91(4H, m), 3.08 (10H, m), 3.49 (4H, m), 7.28–7.50 (5H, m), 7.75 (2H, m),8.23 (1H, m), 9.11 (2H, br).

Example 203N-Ethyl-7-(5-{[2-(2-methoxyphenyl)ethyl]amino}pentanoyl)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxamidehydrochloride

Using7-(5-chloropentanoyl)-N-ethyl-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxamideobtained in Reference Example 124 and 2-(2-methoxyphenyl)ethylamineaccording to the same methods as those of Reference Example 19 andExample 1, the title compound was obtained as colorless crystals havinga melting point of 150 to 151° C.

¹H NMR (300 MHz, DMSO-d₆) δ 1.02 (3H, t, J=7.0 Hz), 1.68 (4H, m), 2.90(4H, m), 3.07 (10H, m), 3.47 (4H, m), 3.80 (3H, s), 6.88–7.02 (2H, m),7.17–7.31 (3H, m), 7.73 (2H, m), 8.23 (1H, m), 9.01 (2H, br).

Example 2045-[[2-(2-Chlorophenyl)ethyl](methyl)amino]-1-[3-(trifluoroacetyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]-1-pentanonehydrochloride

Using5-chloro-1-[3-(trifluoroacetyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]-1-pentanoneobtained in Reference Example 120 andN-[2-(2-chlorophenyl)ethyl]-N-methylamine according to the same methodas that of Example 9, the title compound was obtained as pale yellowamorphous powders.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.54–1.80 (4H, m), 2.34 (3H, s),2.48 (2H, t, J=7.4 Hz), 2.57–2.62 (2H, m), 2.86–3.07 (8H, m), 3.69–3.81(4H, m), 7.11–7.34 (5H, m), 7.75–7.78 (2H, m).

Example 2055-[[2-(2-Chlorophenyl)ethyl](methyl)amino]-1-(2,3,4,5-tetrahydoro-1H-3-benzazepin-7-yl)-1-pentanonedihydrochloride

Potassium carbonate (3.2 g, 23.5 mmol) was added to a solution of5-[[2-(2-chlorophenyl)ethyl](methyl)amino]-1-[3-(trifluoroacetyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]-1-pentanone(1.50 g) obtained in Reference Example 204 in methanol (40 ml)-water (40ml). After stirring at room temperature for 60 minutes, the solvent wasevaporated under reduced pressure, water (100 g) was added, extractedwith ethyl acetate, and washed with brine. The organic layer was driedover anhydrous sodium sulfate, and the solvent was evaporated underreduced pressure to give a free base compound of the title compound as apale yellow oil (1.2 g). A solution of the free base compound in ethanolwas treated with hydrogen chloride (ethyl acetate solution) to give thetitle compound as pale yellow amorphous powders.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.54–1.79 (4H, m), 2.33 (3H, s),2.45 (2H, t, J=7.4 Hz), 2.57–2.62 (2H, m), 2.86–2.97 (13H, m), 7.10–7.34(5H, m), 7.68–7.71 (2H, m).

Example 2061-(3-Acetyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-5-[[2-(2-chlorophenyl)ethyl](methyl)amino]-1-pentanonehydrochloride

Acetyl chloride (54 μl) was added to a solution of5-[[2-(2-chlorophenyl)ethyl](methyl)amino]-1-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-1-pentanone(294 mg) obtained in Example 205 and triethylamine (139 μl) intetrahydrofuran (2 ml). After stirring at room temperature for 60minutes, water (10 g) was added, extracted with ethyl acetate, andwashed with brine. The organic layer was dried over anhydrous sodiumsulfate, the solvent was evaporated under reduced pressure, and purifiedby silica gel column chromatography to give a free base compound of thetitle compound as a pale yellow oil (280 mg). A solution of the freebase compound in ethanol was treated with hydrogen chloride (ethylacetate solution) to give the title compound as pale yellow amorphouspowders (220 mg).

¹H NMR (free-base; 200 MHz, CDCl₃) δ 1.54–1.80 (4H, m), 2.19 (3H, s),2.36 (3H, s), 2.45 (2H, t, J=7.4 Hz), 2.60–2.68 (2H, m), 2.88–3.00 (8H,m), 3.58–3.86 (4H, m),7.12–7.34 (5H, m), 7.73–7.76 (2H, m).

Example 2075-[[2-(2-Chlorophenyl)ethyl](methyl)amino]-1-[3-(methylsulfonyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]-1-pentanonehydrochloride

Methylsulfonyl chloride (45 μl) was added to a solution of5-[[2-(2-chlorophenyl)ethyl](methyl)amino]-1-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-1-pentanone(223 mg) obtained in Example 205 and triethylamine (139 μl) intetrahydrofuran (2 ml). After stirring at room temperature for 60minute, water (10 g) was added, extracted with ethyl acetate, and washedwith brine. The organic layer was dried over anhydrous sodium sulfate,the solvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography to give a free basecompound of the title compound as a pale yellow oil (230 mg). A solutionof the free base compound in ethanol was treated with hydrogen chloride(ethyl acetate solution) to give the title compound as pale yellowamorphous powders (200 mg).

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.54–1.79 (4H, m), 2.34 (3H, s),2.48 (2H, t, J=7.4 Hz), 2.57–2.65 (2H, m), 2.79 (3H, s), 2.86–2.99 (4H,m), 3.08–3.11 (4H, m), 3.43–3.49 (4H, m), 7.11–7.34 (5H, m), 7.74–7.77(2H, m).

Example 2087-{5-[[2-(2-Chlorophenyl)ethyl](methyl)amino]pentanoyl}-N-ethyl-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxamidehydrochloride

Ethyl isocyanate (74 μl) was added to a solution of5-[[2-(2-chlorophenyl)ethyl](methyl)amino]-1-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-1-pentanone (365 mg) obtained in Example 205 intetrahydrofuran (2 ml). After stirring at room temperature for 60minutes, water (10 g) was added, extracted with ethyl acetate, andwashed with brine. The organic layer was dried over anhydrous sodiumsulfate, the solvent was evaporated under reduced pressure, and theresidue was purified by silica gel column chromatography to give a freebase compound of the title compound as a pale yellow oil (330 mg). Asolution of the free base compound in ethanol was treated with hydrogenchloride (ethyl acetate solution) to give the title compound as paleyellow amorphous powders (290 mg).

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.16 (3H, t, J=7.2 Hz), 1.58–1.77(4H, m), 2.38 (3H, s), 2.54 (2H, t, J=7.4 Hz), 2.63–2.69 (2H, m),2.90–3.00 (8H, m), 3.31 (2H, q, J=7.2 Hz), 3.54–3.59 (4H, m), 4.74 (1H,m), 7.11–7.32 (5H, m), 7.69–7.72 (2H, m).

Example 2095-[[2-(2-Methoxyphenyl)ethyl](methyl)amino]-1-[3-(trifluoroacetyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]-1-pentanone

Using5-chloro-1-[3-(trifluoroacetyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]-1-pentanoneobtained in Reference Example 120 andN-[2-(2-methoxyphenyl)ethyl]-N-methylamine according to the same methodas that of Example 9, the title compound was obtained as pale yellowamorphous powders.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.54–1.80 (4H, m), 2.33 (3H, s),2.48 (2H, t, J=7.4 Hz), 2.57–2.62 (2H, m), 2.76–2.80 (2H, m), 2.93–3.06(6H, m), 3.68–3.81 (4H, m), 3.81 (3H, s), 6.86 (2H, t, J=9.2 Hz),7.12–7.27 (3H, m), 7.75–7.78 (2H, m).

Example 2105-[[2-(2-Methoxyphenyl)ethyl](methyl)amino]-1-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-1-pentanonedihydrochloride

Using5-[[2-(2-methoxyphenyl)ethyl](methyl)amino]-1-[3-(trifluoroacetyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]-1-pentanoneobtained in Example 209 according to the same method as that of Example205, the title compound was obtained as pale yellow amorphous powders.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.57–1.79 (4H, m), 2.31 (3H, s),2.45 (2H, t, J=7.4 Hz), 2.53–2.60 (2H, m), 2.74–2.82 (2H, m), 2.91–2.96(11H, m), 3.81 (3H, s), 6.81–6.90 (2H, m), 7.12–7.20 (3H, m), 7.68–7.72(2H, m).

Example 2111-(3-Acetyl-2,3,4-tetrahydro-1H-3-benzazepin-7-yl)-5-[[2-(2-methoxyphenyl)ethyl](methyl)amino]-1-pentanonehydrochloride

Using5-[[2-(2-methoxyphenyl)ethyl](methyl)amino]-1-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-1-pentanoneobtained in Example 210 according to the same method as that of Example206, the title compound was obtained as pale yellow amorphous powders.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.54–1.80 (4H, m), 2.19 (3H, s),2.35 (3H, s), 2.51 (2H, t, J=7.4 Hz), 2.58–2.65 (2H, m), 2.77–2.85 (2H,m), 2.93–3.00 (6H, m), 3.57–3.76 (4H, m), 3.81 (3H, s), 6.82–6.91 (2H,m), 7.12–7.25 (3H, m), 7.73 (2H, m).

Example 2125-[[2-(2-Methoxyphenyl)ethyl](methyl)amino]-1-[3-(methylsulfonyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]-1-pentanonehydrochloride

Using5-[[2-(2-methoxyphenyl)ethyl](methyl)amino]-1-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-1-pentanoneobtained in Example 210 according to the same method as that of Example207, the title compound was obtained as pale yellow amorphous powders.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.56–1.80 (4H, m), 2.36 (3H, s),2.52 (2H, t, J=7.4 Hz), 2.58–2.69 (2H, m), 2.78 (3H, s), 2.75–2.85 (2H,m), 3.06–3.12 (4H, m), 3.43–3.47 (4H, m), 3.81 (3H, s), 6.82–6.91 (2H,m), 7.11–7.27 (3H, m), 7.73 (2H, m).

Example 213N-Ethyl-7-{5-[[2-(2-methoxyphenyl)ethyl](methyl)amino]pentanoyl}-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxamidehydrochloride

Using5-[[2-(2-methoxyphenyl)ethyl](methyl)amino]-1-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-1-pentanoneobtained in Example 210 according to the same method as that of Example208, the title compound was obtained as pale yellow amorphous powders.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.17 (3H, t, J=7.4 Hz), 1.56–1.79(4H, m), 2.36 (3H, s), 2.52 (2H, t, J=7.4 Hz), 2.58–2.69 (2H, m),2.75–2.84 (2H, m), 2.93–3.00 (6H, m), 3.32 (2H, q, J=7.2 Hz), 3.53–3.58(4H, m), 3.81 (3H, s), 4.70 (1H, m), 6.81–6.90 (2H, m), 7.12–7.21 (3H,m), 7.71 (2H, m).

Example 2141-(2-Acetyl-1,2,3,4-tetrahydro-7-isoquinolinyl)-5-[[2-(2-chlorophenyl)ethyl](methyl)amino]-1-pentanonehydrochloride

Using1-(2-acetyl-1,2,3,4-tetrahydro-7-isoquinolinyl)-5-chloro-1-pentanoneobtained in Reference Example 125 andN-[2-(2-chlorophenyl)ethyl]-N-methylamine according to the same methodas that of Example 9, the title compound was obtained as pale yellowamorphous powders.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.54–1.79 (4H, m), 2.19 (3H, s),2.34 (3H, s), 2.48 (2H, t, J=7.0 Hz), 2.57–2.65 (2H, m), 2.87–2.98 (6H,m), 3.69 (2H, t, J=5.8 Hz),4.67 (2H, s), 7.11–7.34 (5H, m), 8.83 (1H,s), 7.74–7.80 (2H, m).

Example 2155-[[2-(2-Chlorophenyl)ethyl](methyl)amino]-1-(1,2,3,4-tetrahydro-7-isoquinolinyl)-1-pentanonedihydrochloride

A solution of(1-(2-acetyl-1,2,3,4-tetrahydro-7-isoquinolinyl)-5-[[2-(2-chlorophenyl)ethyl](methyl)amino]-1-pentanone(5.0 g) obtained in Example 214 in concentrated hydrochloric acid (150ml) was stirred at 130° C. for 2 hours, and the solvent of the reactionmixture was evaporated under reduced pressure to give the crude productof the title compound as a pale yellow solid (4.2 g). Furtherrecrystallization from ethanol-diethyl ether afforded the title compoundas colorless crystals having a melting point of 95° C. (dec).

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.60–1.79 (4H, m), 2.21 (1H, br),2.37 (3H, s), 2.52 (2H, t, J=7.4 Hz), 2.65 (2H, m), 2.88–3.26 (6H, m),3.58 (2H, t, J=5.8 Hz), 4.10 (2H, s), 7.12–7.35 (5H, m), 7.71–7.81 (2H,m).

Example 2165-[[2-(2-Chlorophenyl)ethyl](methyl)amino]-1-[2-(methylsulfonyl)-1,2,3,4-tetrahydro-7-isoquinolinyl]-1-pentanonehydrochloride

Using5-[[2-(2-chlorophenyl)ethyl](methyl)amino]-1-(1,2,3,4-tetrahydro-7-isoquinolinyl)-1-pentanoneobtained in Example 215 according to the same method as that of Example207, the title compound was obtained as pale yellow amorphous powders.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.60–1.79 (4H, m), 2.37 (3H, s),2.52 (2H, t, J=7.4 Hz), 2.65 (2H, m), 2.87 (3H, s), 2.88–3.26 (6H, m),3.58 (2H, t, J=5.8 Hz), 4.50 (2H, s), 7.12–7.35 (5H, m), 7.71–7.81 (2H,m).

Example 2177-{5-[[2-(2-Chlorophenyl)ethyl](methyl)amino]pentanoyl}-N-ethyl-3,4-dihydro-2(1H)-isoquinolinecarboxamidehydrochloride

Using5-[[2-(2-Chlorophenyl)ethyl](methyl)amino]-1-(1,2,3,4-tetrahydro-7-isoquinolinyl)-1-pentanoneobtained in Example 215 according to the same method as that of Example208, the title compound was obtained as pale yellow amorphous powders.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.17 (3H, t, J=5.8 Hz), 1.57–1.78(4H, m), 2.35 (3H, s), 2.48 (2H, t, J=6.6 Hz), 2.63 (2H, m), 2.89–2.99(6H, m), 3.30–3.34 (2H, m), 3.64 (2H, t, J=5.4 Hz), 4.47 (1H, m), 4.58(2H, s), 7.13–7.34 (5H, m), 7.73–7.79 (2H, m).

Example 2181-(2-Acetyl-1,2,3,4-tetrahydro-7-isoqiunolinyl)-5-{[2-(2-chlorophenyl)ethyl]amino}-1-pentanonehydrochloride

Using1-(2-acetyl-1,2,3,4-tetrahydro-7-isoquinolinyl)-5-chloro-1-pentanoneobtained in Reference Example 125 and 2-(2-chlorophenyl)ethylamineaccording to the same methods as those of Reference Example 19 andExample 1, the title compound was obtained as colorless crystals havinga melting point of 78° C. (dec).

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.54–1.79 (4H, m), 2.19 (3H, s),2.37 (1H, br), 2.48 (2H, t, J=7.0 Hz), 2.57–2.65 (2H, m), 2.87–2.98 (6H,m), 3.69 (2H, t, J=5.8 Hz), 4.67 (2H, s), 7.11–7.34 (5H, m), 7.74–7.80(2H, m).

Example 2191-(2-Acetyl-1,2,3,4-tetrahydro-7-isoquinolinyl)-5-{[2-(2-methoxyphenyl)ethyl]amino}-1-pentanonehydrochloride

Using1-(2-acetyl-1,2,3,4-tetrahydro-7-isoquinolinyl)-5-chloro-1-pentanoneobtained in Reference Example 125 and 2-(2-methoxyphenyl)ethylamineaccording to the same methods as those of Reference Example 19 andExample 1, the title compound was obtained as colorless crystals havinga melting point of 78° C. (dec).

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.54–1.79 (4H, m), 2.19 (3H, s),2.37 (1H, br), 2.48 (2H, t, J=7.0 Hz), 2.57–2.65 (2H, m), 2.87–2.98 (6H,m), 3.69 (2H, t, J=5.8 Hz), 3.80 (3H, s), 4.67 (2H, s), 7.11–7.34 (5H,m), 7.74–7.80 (2H, m).

Example 2205-{[2-(2-Chlorophenyl)ethyl]amino}-1-(2,2-dioxide-1,3-dihydro-2,1,3-benzothiadiazol-5-yl)-1-pentanonehydrochloride

Using tert-butyl2-(2-chlorophenyl)ethyl[5-(2,2-dioxide-1,3-dihydro-2,1,3-benzothiadiazol-5-yl)-5-oxopentyl]carbamateobtained in Reference Example 148 according to the same method as thatof Example 1, the title compound was obtained as colorless crystals

MS m/z: 408 [M+H]⁺

Example 2215-{[2-(2-Chlorophenyl)ethyl]amino}-1-(1,3-dimethyl-2,2-dioxide-1,3-dihydro-2,1,3-benzothiadiazol-5-yl)-1-pentanonehydrochloride

Using tert-butyl2-(2-chlorophenyl)ethyl[5-(1,3-dimethyl-2,2-dioxide-1,3-dihydro-2,1,3-benzothiadiazol-5-yl)-5-oxopentyl]carbamateobtained in Reference Example 149 according to the same method as thatof Example 1, the title compound was obtained as colorless crystalshaving a melting point of 149 to 150° C.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.61–1.80 (5H, m), 2.48–2.65 (4H,m), 2.65–2.99 (4H, m), 3.34 (3H, s), 3.35 (3H, s), 6.75 (1H, d, J=8.4Hz), 7.12–7.39 (5H, m), 7.67 (1H, d, J=8.4 Hz).

Example 2225-[[2-(2-Chlorophenyl)ethyl](methyl)amino]-1-(1,3-dimethyl-2,2-dioxide-1,3-dihydro-2,1,3-benzothiadiazol-5-yl)-1-pentanonehydrochloride

Using5-chloro-1-(1,3-dimethyl-2,2-dioxide-1,3-dihydro-2,1,3-benzothiadiazol-5-yl)-1-pentanoneobtained in Reference Example 129 andN-[2-(2-chlorophenyl)ethyl]-N-methylamine according to the same methodas that of Example 9, the title compound was obtained as pale yellowamorphous powders.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.61–1.80 (4H, m), 2.45 (3H, s),2.48–2.65 (4H, m), 2.65–2.99 (4H, m), 3.34 (3H, s), 3.35 (3H, s), 6.75(1H, d, J=8.4 Hz), 7.12–7.39 (5H, m), 7.67 (1H, d, J=8.4 Hz).

Example 2231-(1,3-Dimethyl-2,2-dioxide-1,3-dihydro-2,1,3-benzothiadiazol-5-yl)-5-[[2-(2-methoxyphenyl)ethyl](methyl)amino]-1-pentanonehydrochloride

Using5-chloro-1-(1,3-dimethyl-2,2-dioxide-1,3-dihydro-2,1,3-benzothiadiazol-5-yl)-1-pentanoneobtained in Reference Example 129 andN-[2-(2-chlorophenyl)ethyl]-N-methylamine according to the same methodas that of Example 9, the title compound was obtained as pale yellowamorphous powders.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.60–1.80 (4H, m), 2.34 (3H, s),2.46–2.64 (4H, m), 2.77–2.84 (2H, m), 2.96 (2H, t, J=7.0 Hz), 3.34 (3H,s), 3.35 (3H, s), 3.81 (3H, s), 6.75 (1H, d, J=8.2 Hz), 6.82–6.91 (2H,m), 7.13–7.22 (2H, m), 7.38 (1H, s), 7.67 (1H, d, J=8.2 Hz).

Example 2248-{5-[[2-(2-Chlorophenyl)ethyl](methyl)amino]pentanoyl}-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-onehydrochloride

Using8-(5-chloropentanoyl)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-oneobtained in Reference Example 133 andN-[2-(2-chlorophenyl)ethyl]-N-methylamine according to the same methodas that of Example 9, the title compound was obtained as pale yellowamorphous powders.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.58–1.77 (4H, m), 2.14 (2H, m),2.35 (3H, s), 2.49 (2H, m), 2.58 (2H, m), 2.87–3.00 (6H, m), 3.89 (2H,m), 7.11–7.35 (5H, m), 7.58 (1H, m), 10.91 (1H, s).

Example 2258-{5-[[2-(2-Methoxyphenyl)ethyl](methyl)amino]pentanoyl}-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-onehydrochloride

Using8-(5-chloropentanoyl)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-oneobtained in Reference Example 133 andN-[2-(2-methoxyphenyl)ethyl]-N-methylamine according to the same methodas that of Example 9, the title compound was obtained as colorlesscrystals having a melting point of 187° C. (dec).

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.58–1.77 (4H, m), 2.16 (2H, m),2.36 (3H, s), 2.48–2.67 (4H, m), 2.78–3.00 (6H, m), 3.81 (3H, s), 3.88(2H, m), 6.81–6.90 (3H, m), 7.12–7.16 (2H, m), 7.49 (1H, m), 7.58 (1H,m).

Example 2268-{5-[[2-(2-Chlorophenyl)ethyl](methyl)amino]pentanoyl}-1-methyl-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-onehydrochloride

Using8-(5-chloropentanoyl)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-oneobtained in Reference Example 134 andN-[2-(2-chlorophenyl)ethyl]-N-methylamine according to the same methodas that of Example 9, the title compound was obtained as pale yellowamorphous powders.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.58–1.78 (4H, m), 2.10 (2H, m),2.34 (3H, s), 2.48 (2H, m), 2.60 (2H, m), 2.86–3.00 (5H, m), 3.22 (1H,m), 3.44 (3H, s), 3.84 (2H, m), 6.87 (1H, t, J=8.4 Hz), 7.11–7.34 (4H,m), 7.63 (1H, t, J=8.4 Hz).

Example 2278-{5-[[2-(2-Methoxyphenyl)ethyl](methyl)amino]pentanoyl}-1-methyl-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-onehydrochloride

Using8-(5-chloropentanoyl)-1-methyl-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-oneobtained in Reference Example 134 andN-[2-(2-methoxyphenyl)ethyl]-N-methylamine according to the same methodas that of Example 9, the title compound was obtained as pale yellowamorphous powders.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.59–1.78 (4H, m), 2.10 (2H, m),2.34 (3H, s), 2.45–2.63 (5H, m), 2.78 (2H, m), 2.93 (2H, m), 3.22 (1H,m), 3.44 (3H, s), 3.82 (3H, s), 3.88 (2H, m), 6.82–6.91 (3H, m),7.12–7.34 (2H, m), 7.63 (1H, t, J=8.4 Hz).

Example 228(±)-6-(3-{[2-(2-Chlorophenyl)ethyl]amino}propyl)-1,3-dimethyl-3,6,7,8-tetrahydro-1H-naphtho[2,3-d]imidazole-2,5-dionehydrochloride

Using tert-butyl(±)-2-(2-chlorophenyl)ethyl[3-(1,3-dimethyl-2,5-dioxo-2,3,5,6,7,8-hexahydro-1H-naphtho[2,3-d]imidazol-6-yl)propyl]carbamateobtained in Reference Example 150 according to the same method as thatof Example 1, the title compound was obtained as colorless crystalshaving a melting point of 201 to 203° C.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.58–1.68 (4H, m), 1.93 (3H, m),2.25 (1H, m), 2.51 (2H, m), 2.65 (2H, m), 2.90 (2H, m), 3.03 (2H, m),3.42 (3H, s), 3.43 (3H, s), 6.76 (1H, s), 7.11–7.34 (4H, m), 7.65 (1H,s).

Example 229(±)-6-{3-[[2-(2-Chlorophenyl)ethyl](methyl)amino]propyl}-1,3-dimethyl-3,6,7,8-tetrahydro-1H-naphtho[2,3-d]imidazole-2,5-dionehydrochloride

Using(±)-6-(3-chloropropyl)-1,3-dimethyl-3,6,7,8-tetrahydro-1H-naphtho[2,3-d]imidazole-2,5-dioneobtained in Reference Example 141 andN-[2-(2-chlorophenyl)ethyl]-N-methylamine according to the same methodas that of Example 9, the title compound was obtained as colorlesscrystals having a melting point of 201° C. (dec).

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.58–1.68 (4H, m), 1.93 (2H, m),2.25 (1H, m), 2.36 (3H, s), 2.51 (2H, m), 2.65 (2H, m), 2.90 (2H, m),3.03 (2H, m), 3.42 (3H, s), 3.43 (3H, s), 6.76 (1H, s), 7.11–7.34 (4H,m), 7.65 (1H, s).

Example 230(±)-6-{3-[[2-(2-Methoxyphenyl)ethyl](methyl)amino]propyl}-1,3-dimethyl-3,6,7,8-tetrahydro-1H-naphtho[2,3-d]imidazole-2,5-dionehydrochloride

Using(±)-6-(3-chloropropyl)-1,3-dimethyl-3,6,7,8-tetrahydro-1H-naphtho[2,3-d]imidazole-2,5-dioneobtained in Reference Example 141 andN-[2-(2-methoxyphenyl)ethyl]-N-methylamine according to the same methodas that of Example 9 the title compound was obtained as colorlesscrystals having a melting point of 190 to 191° C.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.56–1.67 (4H, m), 1.94 (2H, m),2.24 (1H, m), 2.36 (3H, s), 2.48 (2H, m), 2.61 (2H, m), 2.80 (2H, m),3.04 (2H, m), 3.41 (3H, s), 3.42 (3H, s), 3.82 (3H, s), 6.76–6.91 (3H,m), 7.13–7.22 (2H, m), 7.65 (1H, s).

Example 231(±)-6-(4-{[2-(2-Chlorophenyl)ethyl]amino}butyl)-1,3-dimethyl-3,6,7,8-tetrahydro-1H-naphtho[2,3-d]imidazole-2,5-dionehydrochloride

Using(±)-6-(4-chlorobutyl)-1,3-dimethyl-3,6,7,8-tetrahydro-1H-naphtho[2,3-d]imidazole-2,5-dioneobtained in Reference Example 142 and 2-(2-chlorophenyl)ethylamineaccording to the same methods as those of Reference Example 19 andExample 1, the title compound was obtained as pale yellow amorphouspowders.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.58–1.68 (6H, m), 1.98 (2H, m),2.22 (1H, m), 2.38 (1H, br), 2.41–2.50 (2H, m), 2.57–2.65 (2H, m),2.87–2.95 (2H, m), 2.99–3.06 (2H, m), 3.41 (3H, s), 3.42 (3H, s), 6.75(1H, s), 7.11–7.34 (4H, m), 7.65 (1H, s).

Example 232(±)-6-{4-([2-(2-Chlorophenyl)ethyl](methyl)amino]butyl}-1,3-dimethyl-3,6,7,8-tetrahydro-1H-naphtho[2,3-d]imidazole-2,5-dionehydrochloride

Using(±)-6-(4-chlorobutyl)-1,3-dimethyl-3,6,7,8-tetrahydro-1H-naphtho[2,3-d]imidazole-2,5-dioneobtained in Reference Example 142 andN-[2-(2-chlorophenyl)ethyl]-N-methylamine according to the same methodas that of Example 9, the title compound was obtained as colorlesscrystals having a melting point of 202 to 204° C.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.58–1.68 (6H, m), 1.98 (2H, m),2.22 (1H, m), 2.34 (3H, s), 2.41–2.50 (2H, m), 2.57–2.65 (2H, m),2.87–2.95 (2H, m), 2.99–3.06 (2H, m), 3.41 (3H, s), 3.42 (3H, s), 6.75(1H, s), 7.11–7.34 (4H, m), 7.65 (1H, s).

Example 233(±)-6-{4-[[2-(2-Methoxyphenyl)ethyl](methyl)amino]butyl}-1,3-dimethyl-3,6,7,8-tetrahydro-1H-naphtho[2,3-d]imidazole-2,5-dionehydrochloride

Using(±)-6-(4-chlorobutyl)-1,3-dimethyl-3,6,7,8-tetrahydro-1H-naphtho[2,3-d]imidazole-2,5-dioneobtained in Reference Example 142 andN-[2-(2-chlorophenyl)ethyl]-N-methylamine according to the same methodas that of Example 9, the title compound was obtained as pale yellowamorphous powders.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.58–1.68 (6H, m), 1.98 (2H, m),2.22 (1H, m), 2.35 (3H, s), 2.44–2.52 (2H, m), 2.57–2.65 (2H, m),2.75–2.84 (2H, m), 3.01–3.06 (2H, m), 3.41 (3H, s), 3.42 (3H, s), 3.82(3H, s), 6.74–6.91 (3H, m), 7.13–7.21 (2H, m), 7.65 (1H, s).

Example 234(±)-2-{3-[[2-(2-Chlorophenyl)ethyl](methyl)amino]propyl}-5,6-dimethoxy-1-indanonehydrochloride

Using (±)-2-(3-chloropropyl)-5,6-dimethoxy-1-indanone obtained inReference Example 146 and N-[2-(2-chlorophenyl)ethyl]-N-methylamineaccording to the same method as that of Example 9, the title compoundwas obtained as pale yellow amorphous powders.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.48 (1H, m), 1.59 (2H, m), 1.94(1H, m), 2.34 (3H, s), 2.47 (2H, t, J=7.6 Hz), 2.58–2.75 (4H, m), 2.90(2H, m) 3.24 (1H, dd, J=17.1, 7.8 Hz), 3.90 (3H, s), 3.96 (3H, s), 6.86(1H, s), 7.08–7.32 (5H, m).

Example 235(±)-5,6-Dimethoxy-2-{3-[[2-(2-methoxyphenyl)ethyl](methyl)amino]propyl}-1-indanonehydrochloride

Using (±)-2-(3-chloropropyl)-5,6-dimethoxy-1-indanone obtained inReference Example 146 and N-[2-(2-methoxyphenyl)ethyl]-N-methylamineaccording to the same method as that of Example 9, the title compoundwas obtained as pale yellow amorphous powders.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.46–1.70 (4H, m), 1.95 (2H, m),2.33 (3H, s), 2.44–2.83 (6H, m), 3.25 (1H, dd, J=17.2, 7.4 Hz), 3.81(3H, s), 3.91 (3H, s), 3.97 (3H, s), 6.81–6.90 (3H, m), 7.12–7.21 (3H,m).

Example 236(±)-2-{4-[[2-(2-Chlorophenyl)ethyl](methyl)amino]butyl}-5,6-dimethoxy-1-indanonehydrochloride

Using (±)-2-(4-chlorobutyl)-5,6-dimethoxy-1-indanone obtained inReference Example 147 and N-[2-(2-chlorophenyl)ethyl]-N-methylamineaccording to the same method as that of Example 9, the title compoundwas obtained as pale yellow amorphous powders.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.45–1.59 (4H, m), 1.99 (2H, m),2.33 (3H, s), 2.45 (2H, t, J=7.6 Hz), 2.54–2.62 (4H, m), 2.80 (2H, m),3.25 (1H, dd, J=17.2, 7.4 Hz), 3.92 (3H, s), 3.96 (3H, s), 6.87 (1H, s),7.11–7.34 (5H, m).

Example 237(±)-5,6-Dimethoxy-2-{4-[[2-(2-methoxyphenyl)ethyl](methyl)amino]butyl}-1-indanonehydrochloride

Using (±)-2-(4-chlorobutyl)-5,6-dimethoxy-1-indanone obtained inReference Example 147 and N-[2-(2-methoxyphenyl)ethyl]-N-methylamineaccording to the same method as that of Example 9, the title compoundwas obtained as pale yellow amorphous powders.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.45–1.59 (4H,m), 1.99 (2H, m),2.32 (3H, s), 2.45 (2H, t, J=7.6 Hz), 2.54–2.62 (4H, m), 2.80 (2H, m),3.25 (1H, dd, J=17.2, 7.4 Hz), 3.80 (3H, s), 3.90 (3H, s), 3.96 (3H, s),6.81–6.91 (3H, m), 7.13–7.21 (3H, m).

Example 2388-[5-(5-Methoxy-3,4-dihydro-2(1H)-isoquinolinyl)pentanoyl]-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-onehydrochloride

Using8-(5-chloropentanoyl)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-oneobtained in Reference Example 133 and5-methoxy-1,2,3,4-tetrahydroisoquinoline according to the same method asthat of Example 9, the title compound was obtained as pale yellowamorphous powders.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.69–1.83 (4H, m), 2.10 (2H, m),2.57 (2H, t, J=6.0 Hz), 2.86 (2H, m), 3.01 (2H, m), 3.18 (2H, m), 3.61(2H, s), 3.80 (3H, s), 3.72–3.90 (4H, m), 6.63–6.69 (2H, m), 6.86 (1H,t, J=8.4 Hz), 7.08 (1H, t, J=8.0 Hz), 7.56 (1H, m), 9.56 (1H, br).

Example 2398-[5-(5-Methoxy-3,4-dihydro-2(1H)-isoquinolinyl)pentanoyl]-1-methyl-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-onehydrochloride

Using8-(5-chloropentanoyl)-1-methyl-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-oneobtained in Reference Example 134 and5-methoxy-1,2,3,4-tetrahydroisoquinoline according to the same method asthat of Example 9, the title compound was obtained as pale yellowamorphous powders.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.69–1.83 (4H, m), 2.05 (2H, m),2.54 (2H, t, J=6.0 Hz), 2.70–2.87 (4H, m), 3.00 (2H, m), 3.22 (2H, t,J=6.0 Hz), 3.42 (3H, s), 3.59 (2H, s), 3.80 (3H, s), 3.81–3.88 (2H, m),6.64 (2H, t, J=8.1 Hz), 6.67 (1H, d, J=8.1 Hz), 7.80 (1H, t, J=7.8 Hz),7.56 (1H, m).

Example 2408-[5-(5-Chloro-3,4-dihydro-2(1H)-isoquinolinyl)pentanoyl]-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-onehydrochloride

Using8-(5-chloropentanoyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-oneobtained in Reference Example 3 and5-chloro-1,2,3,4-tetrahydroisoquinoline according to the same method asthat of Example 9, the title compound was obtained as pale yellowamorphous powders.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.68–1.86 (4H, m), 2.01 (2H, m),2.55 (2H, t, J=7.2 Hz), 2.70–2.83 (6H, m), 2.97 (2H, t, J=7.0 Hz), 3.50(2H, s), 3.58 (2H, s), 3.72 (2H, t, J=6.0 Hz), 6.91 (1H, d, J=7.2 Hz),7.04 (1H, t, J=78 Hz), 717 (1H, t, J=76 Hz), 7.72 (2H, s).

Example 2418-[5-(5-Methoxy-3,4-dihydro-2(1H)-isoquinolinyl)pentanoyl]-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-onehydrochloride

Using8-(5-chloropentanoyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-oneobtained in Reference Example 3 and5-methoxy-1,2,3,4-tetrahydroisoquinoline according to the same method asthat of Example 9, the title compound was obtained as pale yellowamorphous powders.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.66–1.85 (4H, m), 1.98 (2H, m),2.54 (2H, t, J=7.0 Hz), 2.71–2.81 (6H, m), 2.97 (2H, t, J=6.6 Hz), 3.48(2H, s), 3.58 (2H, s), 3.72 (2H, t, J=6.4 Hz), 3.80 (3H, s), 6.64 (2H,t, J=7.0 Hz), 7.08 (1H, t, J=7.6 Hz), 7.73 (2H, s).

Example 2421-(1,3-Dimethyl-2,2-dioxide-1,3-dihydro-2,1,3-benzothiadiazol-5-yl)-5-(5-methoxy-3,4-dihydro-2(1H)-isoquinolinyl)-1-pentanonehydrochloride

Using5-chloro-1-(1,3-dimethyl-2,2-dioxide-1,3-dihydro-2,1,3-benzothiadiazol-5-yl)-1-pentanoneobtained in Reference Example 129 and5-methoxy-1,2,3,4-tetrahydroisoquinoline according to the same method asthat of Example 9, the title compound was obtained as pale yellowamorphous powders.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.68–1.85 (4H, m), 2.58 (2H, t,J=7.0 Hz), 2.72 (4H, m), 2.98 (2H, t, J=7.4 Hz), 3.29 (3H, s), 3.30 (3H,s), 3.58 (2H, s), 3.79 (3H, s), 6.61–6.66 (3H, m), 7.08 (1H, t, J=8.0Hz), 7.34 (1H, m), 7.65 (1H, m).

Example 243(±)-2-[4-(5-Chloro-3,4-dihydro-2(1H)-isoquinolinyl)butyl]-5,6-dimethoxy-1-indanone

Using (±)-2-(4-chlorobutyl)-5,6-dimethoxy-1-indanone obtained inReference Example 147 and 5-chloro-1,2,3,4-tetrahydroisoquinolineaccording to the same method as that of Example 9, the title compoundwas obtained as pale yellow amorphous powders.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.49–1.68 (4H, m), 1.95 (2H, m),2.52 (2H, t, J=7.6 Hz), 2.62–2.78 (4H, m), 2.87 (2H, m), 3.24 (1H, dd,J=16.8, 7.2 Hz), 3.59 (2H, s), 3.90 (3H, s), 3.96 (3H, s), 6.87–6.94(2H, m), 7.05 (1H, t, J=7.8 Hz), 7.18 (2H, m).

Example 244(±)-5,6-Dimethoxy-2-[4-(5-methoxy-3,4-dihydro-2(1H)-isoquinolinyl)butyl]-indanone

Using (±)-2-(4-chlorobutyl)-5,6-dimethoxy-1-indanone obtained inReference Example 147 and 5-methoxy-1,2,3,4-tetrahydroisoquinolineaccording to the same method as that of Example 9, the title compoundwas obtained as pale yellow amorphous powders.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.50–1.68 (4H, m), 1.97 (2H, m),2.51 (2H, t, J=8.2 Hz), 2.62–2.76 (6H, m), 3.23 (1H, dd, J=17.2, 7.6Hz), 3.59 (2H, s), 3.80 (3H, s), 3.90 (3H, s), 3.96 (3H, s), 6.62–6.67(2H, m), 6.87 (1H, s), 7.08 (1H, t, J=7.8 Hz), 7.17 (1H, s).

Example 2458-(5-{[2-(1H-indol-3-yl)ethyl]amino}pentanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using tert-butyl2-(1H-indol-3-yl)ethyl[5-oxo-5-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)pentyl]carbamate(822 mg) obtained in Reference Example 151 according to the same methodas that of Example 1, the title compound was obtained as colorlesscrystals (630 mg) having a melting point of 179 to 180° C.

¹H NMR (300 MHz, DMSO-d₆) δ 1.55–1.80 (4H, m), 2.59 (2H, t, J=7.8 Hz),2.80–3.25 (12H, m), 3.98 (2H, t, J=8.4 Hz), 7.00 (1H, t, J=7.8 Hz), 7.09(1H, t, J=7.8 Hz), 7.24 (1H, d, J=2.1 Hz), 7.37 (1H, d, J=7.8 Hz), 7.61(1H, d, J=7.8 Hz), 7.73 (1H, s), 7.74 (1H, s), 9.00–9.20 (2H, br), 11.0(1H, s).

Example 246(±)-8-{5-[(2-Hydroxy-2-phenyethyl)amino]pentanoyl}-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using tert-butyl(±)-2-hydroxy-2-phenylethyl][5-oxo-5-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)pentyl]carbamate(1.29 g) obtained in Reference Example 152 according to the same methodas that of Example 1, the title compound was obtained as pale yellowcrystals (680 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.55–1.80 (4H, m), 2.59 (2H, t, J=7.8 Hz),2.90–3.25 (10H, m), 3.99 (2H, t, J=8.4 Hz), 4.98 (1H, d, J=8.4 Hz),6.10–6.30 (1H, br), 7.30–7.50 (5H, m), 7.73 (1H, s), 7.74 (1H, s),8.85–9.25 (2H, br).

Example 247(±)-8-(5-([2-Hydroxy-2-(3-hydroxyphenyl)ethyl]amino}pentanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using tert-butyl(±)-2-hydroxy-2-(3-hydroxyphenyl)ethyl[5-oxo-5-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)pentyl]carbamate(201 mg) obtained in Reference Example 153 according to the same methodas that of Example 1, the title compound was obtained as colorlesscrystals (169 mg) having a melting point of 178 to 179° C.

¹H NMR (300 MHz, DMSO-d₆) δ 1.55–1.80 (4H, m), 2.59 (2H, t, J=7.8 Hz),2.80–3.60 (10H, m), 3.99 (2H, t, J=8.4 Hz), 4.90 (1H, d, J=9.9 Hz),5.90–6.30 (1H, br), 6.65–6.90 (3H, m), 7.16 (1H, t, J=7.8 Hz), 7.73 (1H,s), 7.74 (1H, s), 8.65–8.85 (1H, br), 9.00–9.25 (1H, br), 9.40–9.65 (1H,br).

Example 2488-(5-{[2-(2-Chloro-4-fluorophenyl)ethyl]amino}pentanoyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-onehydrochloride

Using tert-butyl2-(2-chloro-4-fluorophenyl)ethyl[5-oxo-5-(2-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)pentyl]carbamante(440 mg) obtained in Reference Example 155 according to the same methodsas that of Example 1, the title compound (282 mg) was obtained as paleyellow crystals having a melting point of 128 to 129° C. (dec).

¹H NMR (400 MHz, DMSO-d₆) δ 1.52–1.73 (4H, m), 1.90–1.94 (2H, m), 2.77(2H, t, J=7 Hz), 2.95–3.09 (8H, m), 3.57 (2H, s), 3.60 (2H, t, J=6 Hz),7.22 (1H, dt, J=2.7, 8.5 Hz), 7.43–7.47 (2H, m), 7.71 (1H, s), 7.75 (1H,s), 9.22 (2H, s). IR (KBr) νcm⁻¹: 3491, 2945, 2774, 1712, 1671, 1604,1495, 1346, 1153.

Example 2491-(1-Acetyl-2,3-dihydro-1H-indol-5-yl)-5-{[2-(2-chloro-4-fluorophenyl)ethyl]amino}pentan-1-onehydrochloride

Using tert-butyl5-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-5-oxopentyl[2-(2-chloro-4-fluorophenyl)ethyl]carbamate(540 mg) obtained in Reference Example 156 according to the same methodas that of Example 1, the title compound (275 mg) was obtained ascolorless crystals having a melting point of 176 to 177° C. (dec).

¹H NMR (400 MHz, DMSO-d₆) δ 1.51–1.73 (4H, m), 2.18 (3H, s), 2.95–3.08(8H, m), 3.17 (2H, t, J=8.3 Hz), 4.14 (2H, t, J=8.5 Hz), 7.22 (1H, dt,J=2.7, 8.5 Hz), 7.43–7.47 (2H, m), 7.82 (1H, s), 7.83 (1H, t, J=8.0 Hz),8.08 (1H, d, J=8.5 Hz), 9.17 (2H, s). IR (KBr) νcm⁻¹: 3436, 2954, 2780,1667, 1604, 1494, 1442, 1403, 1338, 1260, 1233.

Example 2506-(5-{[2-(2-Chloro-4-fluorophenyl)ethyl]amino}pentanoyl)-1-methyl-3,4-dihydroquinolin-2(1H)-onehydrochloride

Using tert-butyl2-(2-chloro-4-fluorophenyl)ethyl[5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-5-oxopentyl]carbamate(460 mg) obtained in Reference Example 157 according to the same methodas that of Example 1, the title compound (356 mg) was obtained as paleyellow crystals having a melting point of 169 to 170° C. (dec).

¹H NMR (400 MHz, DMSO-d₆) δ 1.58–1.65 (4H, m), 2.49 (2H, t, J=7.0 Hz),2.83–3.04 (10H, m), 3.19 (3H, s), 7.09 (1H, d, J=8.5 Hz), 7.13 (1H, dt,J=2.6, 8.5 Hz), 7.33–7.40 (2H, m), 7.76 (1H, s), 7.80 (1H, d, J=8.3 Hz),9.33 (2H, s). IR (KBr) νcm⁻¹: 3433, 2953, 2790, 1673, 1603, 1494, 1354,1128.

Example 2518-[5-({2-[2-(Trifluoromethoxy)phenyl]ethyl}amino)pentanoyl]-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-onehydrochloride

Using tert-butyl5-oxo-5-(2-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)pentyl}2-[2-(trifluoromethoxy)phenyl]ethyl)carbamate(200 mg) obtained in Reference Example 158 according to the same methodas that of Example 1, the title compound (95 mg) was obtained as paleyellow crystals having a melting point of 71 to 72° C. (dec).

¹H NMR (400 MHz, DMSO-d₆) δ 1.66–1.68 (4H, m), 1.89–1.95 (2H, m), 2.77(2H, t, J=6 Hz), 2.97–3.06 (8H, m), 3.58 (2H, s), 3.61 (2H, t, J=6 Hz),7.35–7.47 (4H, m), 7.72 (1H, s), 7.76 (1H, s), 9.06 (2H, brs). IR (KBr)νcm⁻¹: 3422, 2943, 1711, 1605, 1496, 1344, 1256, 1154.

Example 2521-(1-Acetyl-2,3-dihydro-1H-indol-5-yl)-5-({2-[2-(trifluoromethoxy)phenyl]ethyl}amino)pentan-1-onehydrochloride

Using tert-butyl5-(1-acetyl-2,3-dihydro-1H-indol-yl)-5-oxopentyl{2-[2-(trifluoromethoxy)phenyl]ethyl}carbamate(450 mg) obtained in Reference Example 159 according to the same methodas that of Example 1, the title compound (274 mg) was obtained ascolorless crystals having a melting point of 180 to 182° C. (dec).

¹H NMR (400 MHz, DMSO-d₆) δ 1.65–1.71 (4H, m), 2.18 (3H, s), 2.96–3.07(8H, m), 3.17 (2H, t, J=8.3 Hz), 4.14 (2H, t, J=8.3 Hz), 7.35–7.48 (4H,m), 7.82 (1H, s), 7.83 (1H, t, J=8.3 Hz), 8.08 (1H, d, J=8.3 Hz), 9.20(2H, br.s). IR (KBr) νcm⁻¹: 3432, 2953, 2766, 1676, 1601, 1492, 1442,1398, 1260, 1177.

Example 2531-Methyl-6-[5-({2-[2-(trifluoromethoxy)phenyl]ethyl}amino)pentanoyl]-3,4-dihydroquinolin-2(1H)-onehydrochloride

Using tert-butyl5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-5-oxopentyl{2-[2-(trifluoromethoxy)phenyl]ethyl}carbamate(435 mg) obtained in Reference Example 160 according to the same methodas that of Example 1, the title compound (237 mg) was obtained ascolorless crystals having a melting point of 89 to 90° C. (dec).

¹H NMR (400 MHz, DMSO-d₆) δ 1.62–1.69 (4H, m), 2.58 (2H, t, J=7.0 Hz),2.92–3.07 (10H, m), 3.28 (3H, s), 7.19 (1H, d, J=8.5 Hz), 7.35–7.48(4H,m), 7.84 (1H, s), 7.89 (1H, d, J=8.3 Hz), 9.11 (2H, br.s). IR (KBr)νcm⁻¹: 3432, 2944, 1675, 1604, 1456, 1364, 1265, 1131.

Example 2541,3-Dimethyl-5-[5-({2-[2-(trifluoromethoxy)phenyl]ethyl}amino)pentanoyl]-1,3-dihydro-2H-benzimidazol-2-onehydrochloride

Using tert-butyl5-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-5-oxopentyl{2-[2-(trifluoromethoxy)phenyl]ethyl}carbamate(240 mg) obtained in Reference Example 161 according to the same methodas that of Example 1, the title compound (127 mg) was obtained ascolorless crystals having a melting point of 133 to 134° C. (dec).

¹H NMR (400 MHz, DMSO-d₆) δ 1.70–1.74 (4H, m), 2.98 (2H, br.s),3.08–3.11 (6H, m), 3.36 (3H, s), 3.38 (3H, s), 7.24 (1H, d, J=8.3 Hz),7.35–7.43 (3H, m), 7.46 (1H, dd, J=2.2, 7.0 Hz), 7.72 (1H, d, J=1.5 Hz),7.80 (1H, dd, J=1.5, 8.3 Hz), 9.19 (2H, br.s). IR (KBr) νcm⁻¹: 3496,2954, 2782, 1720, 1675, 1513, 1456, 1255, 1213, 1178.

Example 2558-(5-{[3-(2-Methoxyphenyl)propyl]amino}pentanoyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-onehydrochloride

Using tert-butyl3-(2-methoxyphenyl)propyl[5-oxo-5-(2-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)pentyl]carbamate(160 mg) obtained in Reference Example 162 according to the same methodas that of Example 1, the title compound (113 mg) was obtained as paleyellow amorphous powders.

¹H NMR (400 MHz, DMSO-d₆) δ 1.64 (4H, br.s), 1.72–1.95 (4H, m), 2.59(2H, t, J=6 Hz), 2.70–2.93 (6H, m), 2.98 (2H, br.s), 3.57 (2H, s), 3.60(2H, br.s), 3.77 (3H, s), 6.87 (1H, t, J=7.3 Hz), 6.95 (1H, d, J=7.6Hz), 7.14 (1H, d, J=7.3 Hz), 7.19 (1H, t, J=7.6 Hz), 7.71 (1H, s), 7.75(1H, s), 8.81 (2H, br.s). IR (KBr) νcm⁻¹: 3425, 2945, 1708, 1664, 1601,1495, 1344, 1244, 1155, 759.

Example 2561-(1-Acetyl-2,3-dihydro-1H-indol-5-yl)-5-{[3-(2-methoxyphenyl)propyl]amino}pentan-1-onehydrochloride

Using tert-butyl5-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-5-oxopentyl[3-(2-methoxyphenyl)propyl]carbamate(410 mg) obtained in Reference Example 163 according to the same methodas that of Example 1, the title compound (290 mg) was obtained ascolorless crystals having a melting point of 165 to 166° C. (dec).

¹H NMR (400 MHz, DMSO-d₆) δ 1.62–1.68 (4H, m), 1.85–1.95 (2H, m), 2.18(3H, s), 2.59 (2H, t, J=7.3 Hz), 2.79–2.87 (4H, m), 2.98 (2H, t, J=7Hz), 3.16 (2H, t, J=8.3 Hz), 3.77 (3H, s), 4.13 (2H, t, J=8.3 Hz), 6.89(1H, t, J=7.6 Hz), 6.94 (1H, d, J=7.6 Hz), 7.15 (1H, d, J=7.6 Hz), 7.19(1H, t, J=7.6 Hz), 7.81 (1H, s), 7.82 (1H, d, J=8.3 Hz), 8.08 (1H, d,J=8.3 Hz), 9.00 (2H, br.s). IR (KBr) νcm⁻¹: 3436, 2945, 1676, 1661,1602, 1492, 1438, 1399, 1334, 1243, 754.

Example 2576-(5-{[3-(2-Methoxyphenyl)propyl]amino}pentanoyl)-1-methyl-3,4-dihydroquinolin-2(1H)-onehydrochloride

Using tert-butyl3-(2-methoxyphenyl)propyl[5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-5-oxopentyl]carbamate(410 mg) obtained in Reference Example 164 according to the same methodas that of Example 1, the title compound (295 mg) was obtained ascolorless crystals having a melting point of 88 to 89° C. (dec).

¹H NMR (400 MHz, DMSO-d₆) δ 1.57 (4H, br.s), 1.78–1.84 (2H, m),2.47–2.53 (4H, m), 2.75–2.80 (4H, m), 2.85 (2H, t, J=7 Hz), 2.93 (2H, t,J=7 Hz), 3.19 (3H, s), 3.69 (3H, s), 6.79 (1H, t, J=7.3 Hz), 6.87 (1H,d, J=7.3 Hz), 7.07 (1H, d, J=7.3 Hz), 7.10 (1H, d, J=8.3 Hz), 7.11 (1H,t, J=7.3 Hz), 7.75 (1H, s), 7.81 (1H, d, J=8.3 Hz), 8.88 (2H, br.s). IR(KBr) νcm⁻¹: 3434, 2948, 1672, 1603, 1495, 1464, 1360, 1245, 1128, 750.

Example 2585-(5-{[3-(2-Methoxyphenyl)propyl]amino}pentanoyl)-1,3-dimethyl-1,3-dihydro-2H-benzimidazol-2-onehydrochloride

Using tert-butyl5-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-5-oxopentyl[3-(2-methoxyphenyl)propyl]carbamate(380 mg) obtained in Reference Example 165 according to the same methodas that of Example 1, the title compound (186 mg) was obtained as paleyellow amorphous powders.

¹H NMR (400 MHz, DMSO-d₆) δ 1.53–1.63 (4H, m), 1.77–1.85 (2H, m), 2.51(2H, t, J=7.5 Hz), 2.76–2.81 (4H, m), 2.98 (2H, t, J=6.6 Hz), 3.26 (3H,s), 3.29 (3H, s), 3.69 (3H, s), 6.78 (1H, t, J=7.3 Hz), 6.87 (1H, d,J=7.5 Hz), 7.06 (1H, d, J=7.5 Hz), 7.10 (1H, t, J=7.3 Hz), 7.15 (1H, d,J=8.3 Hz), 7.62 (1H, d, J=1.5 Hz), 7.70 (1H, dd, J=1.5, 8.3 Hz), 8.92(2H, br.s). IR (KBr) νcm⁻¹: 3443, 2943, 1715, 1673, 1621, 1512, 1495,1462, 1244, 1200, 758.

Example 2598-(5-{[2-(2-Ethoxyphenoxy)ethyl]amino}pentanoyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-onehydrochloride

Using tert-butyl2-(2-ethoxyphenoxy)ethyl[5-oxo-5-(2-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)pentyl]carbamate(205 mg) obtained in Reference Example 166 according to the same methodas that of Example 1, the title compound (152 mg) was obtained ascolorless crystals having a melting point of 110 to 113° C. (dec).

¹H NMR (400 MHz, DMSO-d₆) δ 1.31 (3H, t, J=6.6 Hz), 1.69 (4H, br.s),1.91 (2H, br.s), 2.76 (2H, br.s), 3.00–3.08 (4H, m), 3.29 (2H, br.s),3.57 (2H, s), 3.60 (2H, br.s), 4.01 (2H, q, J=6.6 Hz), 4.26 (2H, br.s),6.88–7.04 (4H, m), 7.71 (1H, s), 7.75 (1H, s), 9.16 (2H, br.s). IR (KBr)νcm⁻¹: 3418, 2940, 1708, 1671, 1603, 1507, 1348, 1254, 1213, 1155, 1127,740.

Example 2601-(1-Acetyl-2,3-dihydro-1H-indol-5-yl)-5-{[2-(2-ethoxyphenoxy)ethyl]amino}pentan-1-onehydrochloride

Using tert-butyl5-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-5-oxopentyl[2-(2-ethoxyphenoxy)ethyl]carbamate(390 mg) obtained in Reference Example 167 according to the same methodas that of Example 1, the title compound (275 mg) was obtained ascolorless crystals having a melting point of 125 to 126° C. (dec).

¹H NMR (400 MHz, DMSO-d₆) δ 1.31 (3H, t, J=6.8 Hz), 1.65–1.71 (4H, m),2.18 (3H, s), 2.99–3.18 (6H, m), 3.28 (2H, br.s), 4.01 (2H, q, J=6.8Hz), 4.13 (2H, t, J=8.3 Hz), 4.28 (2H, t, J=6 Hz), 6.85–7.04 (4H, m),7.81 (1H, s), 7.82 (1H, d, J=8 Hz), 8.08 (1H, d, J=8 Hz), 9.30 (2H, s).IR (KBr) νcm⁻¹: 3498, 2943, 1683, 16424, 1598, 1509, 1488, 1448, 1407,1254, 1209, 1126, 746.

Example 2616-(5-{[2-(2-Ethoxyphenoxy)ethyl]amino}pentanoyl)-1-methyl-3,4-dihydroquinolin-2(1H)-onehydrochloride

Using tert-butyl2-(2-ethoxyphenoxy)ethyl[5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-5-oxopentyl]carbamate(420 mg) obtained in Reference Example 168 according to the same methodas that of Example 1, the title compound (292 mg) was obtained ascolorless crystals having a melting point of 135 to 136° C. (dec).

¹H NMR (400 MHz, DMSO-d₆) δ 1.31 (3H, t, J=6.8 Hz), 1.65–1.76 (4H, m),2.57 (2H, t, J=6 Hz), 2.93 (2H, t, J=7 Hz), 3.04 (2H, t, J=7 Hz), 3.09(2H, br.s), 3.27 (3H, s), 3.29 (2H, t, J=6 Hz), 4.01 (2H, q, J=6.8 Hz),4.28 (2H, t, J=6 Hz), 6.85–7.05 (4H, m), 7.18 (1H, d, J=8.3 Hz), 7.83(1H, s), 7.89 (1H, d, J=8.3 Hz), 9.27 (2H, s). IR (KBr) νcm⁻¹: 3436,2954, 1671, 1605, 1508, 1455, 1358, 1256, 1220, 1130, 744.

Example 2625-(5-{[2-(2-Ethoxyphenoxy)ethyl]amino}pentanoyl)-1,3-dimethyl-1,3-dihydro-2H-benzimidazol-2-onehydrochloride

Using tert-butyl5-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-5-oxopentyl[2-(2-ethoxyphenoxy)ethyl]carbamate(260 mg) obtained in Reference Example 169 according to the same methodas that of Example 1, the title compound (156 mg) was obtained ascolorless crystals having a melting point of 103 to 105° C. (dec).

¹H NMR (400 MHz, DMSO-d₆) δ 1.31 (3H, t, J=6.8 Hz), 1.67–1.77 (4H, m),3.09 (4H, t, J=7 Hz), 3.30 (2H, t, J=7.5 Hz), 3.36 (3H, s), 3.37 (3H,s), 4.00 (2H, q, J=6.8 Hz), 4.27 (2H, t, J=5.3 Hz), 6.85–7.00 (3H, m),7.03 (1H, dd, J=1.7, 7.8 Hz), 7.24 (1H, d, J=8.3 Hz), 7.72 (1H, d, J=1.5Hz), 7.79 (1H, dd, J=1.5, 8.3 Hz), 9.23 (2H, br.s). IR (KBr) νcm⁻¹:3527, 2942, 2742, 1719, 1667, 1620, 1506, 1456, 1249, 1202, 1128, 737.

Example 2638-[5-({2-[(2-Ethoxyphenyl)amino]ethyl}amino)pentanoyl]-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-onedihydrochloride

Using tert-butyl2-[(2-ethoxyphenyl)amino]ethyl[5-oxo-5-(2-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)pentyl]carbamate(605 mg) obtained in Reference Example 170 according to the same methodas that of Example 1, the title compound (431 mg) was obtained ascolorless crystals having a melting point of 98 to 100° C. (dec).

¹H NMR (400 MHz, DMSO-d₆) δ 1.36 (3H, t, J=6.8 Hz), 1.65–1.71 (4H, m),1.88–1.94 (2H, m), 2.76 (2H, t, J=6.0 Hz), 2.94–3.00 (4H, m), 3.11 (2H,br.s), 3.51 (2H, t, J=6.6 Hz), 3.57 (2H, s), 3.60 (2H, t, J=6.0 Hz),4.04 (2H, q, J=6.8 Hz), 6.26 (2H, br) 6.80–6.86 (2H, m), 6.91–6.93 (2H,m), 7.71 (1H, s), 7.75 (1H, s), 9.27 (2H, s). IR (KBr) νcm⁻¹: 3392,2774, 1709, 1665, 1606, 1496, 1344, 1267, 1162, 1040, 766.

Example 2641-(1-Acetyl-2,3-dihydro-1H-indol-5-yl)-5-({2-[(2-ethoxyphenyl)amino]ethyl}amino)pentan-1-onedihydrochloride

Using tert-butyl5-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-5-oxopentyl{2-[(2-ethoxyphenyl)amino]ethyl}carbamate(690 mg) obtained in Reference Example 171 according to the same methodas that of Example 1, the title compound (545 mg) was obtained ascolorless crystals having a melting point of 155 to 157° C. (dec).

¹H NMR (400 MHz, DMSO-d₆) δ 1.36 (3H, t, J=6.8 Hz), 1.64–1.70 (4H, m),2.18 (3H, s), 2.95 (2H, br.s), 3.00 (2H, t, J=6.8 Hz), 3.13–3.19 (4H,m), 3.53 (2H, t, J=6.6 Hz), 4.05 (2H, q, J=6.8 Hz), 4.14 (2H, t, J=8.5Hz), 6.85–7.02 (4H, m), 6.94 (2H, br) 7.82 (1H, s), 7.83 (1H, d, J=8.3Hz), 8.07 (1H, d, J=8.3 Hz), 9.36 (2H, s). IR (KBr) νcm⁻¹: 3546, 3467,2748, 1678, 1600, 1504, 1439, 1393, 1322, 1265, 1122, 1042, 762.

Example 2655-[5-({2-[(2-Ethoxyphenyl)amino]ethyl}amino)pentanoyl]-1,3-dimethyl-1,3-dihydro-2H-benzimidazol-2-onedihydrochloride

Using tert-butyl 5-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-5-oxopentyl{2-[(2-ethoxyphenyl)amino]ethyl}carbamate (660 mg) obtained in Reference Example 171according to the same method as that of Example 1, the title compound(448 mg) was obtained as colorless crystals having a melting point of173 to 175° C. (dec).

¹H NMR (400 MHz, DMSO-d₆) δ 1.36 (3H, t, J=7.0 Hz), 1.65–1.73 (4H, m),2.97 (2H, br.s), 3.08 (2H, t, J=6.8 Hz), 3.13 (2H, br.s), 3.35 (3H, s),3.37 (3H, s), 3.53 (2H, t, J=6.5 Hz), 4.05 (2H, q, J=7.0 Hz), 6.85–7.02(4H, m), 7.24 (1H, d, J=8.3 Hz), 7.46 (2H, br) 7.72 (1H, s), 7.79 (1H,d, J=8.3 Hz), 9.39 (2H, s). IR (KBr) νcm⁻¹: 3423, 2749, 1718, 1673,1619, 1506, 1394, 1263, 1200, 1041, 767.

Example 2668-{3-[1-(2-Phenylethyl)-4-piperidinyl]propanoyl}-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-onehydrochloride

Using8-[3-(4-piperidinyl)propanoyl]-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-one(312 mg) obtained in Reference Example 174 and (2-bromoethyl)benzene(185 mg) according to the same method as that of Example 81, the titlecompound was obtained as pale yellow crystals (285 mg) having a meltingpoint of 207 to 208° C.

¹H NMR (free base; 400 MHz, CDCl₃) δ 1.42–1.47 (3H, m), 1.69–1.80 (4H,m), 2.01–2.13 (4H, m), 2.64–2.68 (2H, m), 2.81–2.88 (4H, m), 2.95 (2H,t, J=7.6 Hz), 3.10 (2H, d J=11.5 Hz), 3.55 (2H, s), 3.74 (2H, t, J=6Hz), 7.18–7.30 (5H, m), 7.73 (2H, s). IR (KBr) νcm⁻¹: 1715, 1672, 1604,1343, 1152.

Example 2678-(3-{1-[2-(2-Methoxyphenyl)ethyl]-4-piperidinyl}propanoyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-onehydrochloride

Using8-[3-(4-piperidinyl)propanoyl]-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-one(312 mg) obtained in Reference Example 174 and 2-(2-methoxyphenyl)ethylmethanesulfonate (230 mg) according to the same method as that ofExample 81, the title compound was obtained as pale yellow amorphouspowders (184 mg).

¹H NMR (free base; 400 MHz, CDCl₃) δ 1.30–1.40 (3H, m), 1.67–1.76 (4H,m), 1.97–2.07 (4H, m), 2.51–2.55 (2H, m), 2.80–2.84 (4H, m), 2.94 (2H,t, J=7.5 Hz), 3.03 (2H, d, J=11.0 Hz), 3.55 (2H, s), 3.74 (2H, t, J=6Hz), 3.81(3H, s), 6.83–6.89 (2H, m), 7.13–7.20 (2H, m), 7.73 (2H, s). IR(KBr) νcm⁻¹: 1717, 1673, 1604, 1495, 1343, 1243, 1153.

Example 2688-(3-{1-[2-(2-Methylphenyl)ethyl]-4-piperidinyl}propanoyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-onehydrochloride

Using8-[3-(4-piperidinyl)propanoyl]-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-oneobtained in Reference Example 174 and 2-(2-methylphenyl)ethylmethanesulfonate according to the same method as that of Example 81, thetitle compound was obtained as pale yellow amorphous powders.

¹H NMR (free base; 400 MHz, CDCl₃) δ 1.30–1.40 (3H, m), 1.68–1.78 (4H,m), 1.99–2.07 (4H, m), 2.32 (3H, s), 2.49–2.53 (2H, m), 2.79–2.85 (4H,m), 2.95 (2H, t, J=7.5 Hz), 3.06 (2H, d, J=10.7 Hz), 3.55 (2H, s), 3.74(2H, t, J=6 Hz), 7.09–7.15 (4H, m), 7.73 (2H, s). IR (KBr) νcm⁻¹: 1717,1673, 1.604, 1495, 1342, 1153.

Example 2698-(3-{1-[2-(2-Chlorophenyl)ethyl]-4-piperidinyl}propanoyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-²(1H)-onehydrochloride

Using8-[3-(4-piperidinyl)propanoyl]-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-oneobtained in Reference Example 174 and 2-(2-chlorophenyl)ethylmethanesulfonate according to the same method as that of Example 81, thetitle compound was obtained as pale yellow amorphous powders.

¹H NMR (free base; 400 MHz, CDCl₃) δ 1.30–1.40 (3H, m), 1.68–1.78 (4H,m), 2.01–2.07 (4H, m), 2.55–2.59 (2H, m), 2.82 (2H, t, J=6 Hz),2.93–2.96 (4H, m), 3.03 (2H, d, J=11.0 Hz), 3.55 (2H, s), 3.74 (2H, t,J=6 Hz), 7.13–7.34 (4H, m), 7.73 (2H, s). IR (KBr) νcm⁻¹: 1716, 1673,1604, 1496, 1342, 1152.

Example 2708-(3-{1-[2-(3-Methoxyphenyl)ethyl]-4-piperidinyl}propanoyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-onehydrochloride

Using8-[3-(4-piperidinyl)propanoyl]-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-oneobtained in Reference Example 174 and 2-(3-methoxyphenyl)ethylmethanesulfonate according to the same method as that of Example 81, thetitle compound was obtained as pale yellow amorphous powders.

¹H NMR (free base; 400 MHz, CDCl₃) δ 1.30–1.39 (3H, m), 1.68–1.77 (4H,m), 1.97–2.07 (4H, m), 2.55–2.59 (2H, m), 2.77–2.84 (4H, m), 2.93–3.02(4H, m), 3.55 (2H, s), 3.74 (2H, t, J=6 Hz), 3.79 (3H, s), 6.73–6.80(3H, m), 7.20 (1H, t, J=8 Hz), 7.73 (2H, s). IR (KBr) νcm⁻¹: 1717, 1673,1603, 1342, 1152.

Example 2718-(3-{1-[2-(3-Methylphenyl)ethyl]-4-piperidinyl}propanoyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-onehydrochloride

Using8-[3-(4-piperidinyl)propanoyl]-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-oneobtained in Reference Example 174 and 2-(3-methylphenyl)ethylmethanesulfonate according to the same method as that of Example 81, thetitle compound was obtained as pale yellow amorphous powders.

¹H NMR (free base; 400 MHz, CDCl₃) δ 1.30–1.39 (3H, m), 1.68–1.77 (4H,m), 1.97–2.07 (4H, m), 2.32 (3H, s), 2.54–2.58 (2H, m), 2.75–2.85 (4H,m), 2.93–3.03 (4H, m), 3.55 (2H, s), 3.74 (2H, t, J=6 Hz), 6.99–7.04(3H, m), 7.17 (1H, t, J=8 Hz), 7.73 (2H, s). IR (KBr) νcm⁻¹: 1719, 1673,1605, 1342, 1152.

Example 2728-(3-{1-[2-(3-Chlorophenyl)ethyl]-4-piperidinyl}propanoyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-onehydrochloride

Using8-[3-(4-piperidinyl)propanoyl]-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-one(312 mg) obtained in Reference Example 174 and 2-(3-chlorophenyl)ethylmethanesulfonate (235 mg) according to the same method as that ofExample 81, the title compound was obtained as pale yellow crystals (200mg) having a melting point of 108 to 109° C.

¹H NMR (free base; 400 MHz, CDCl₃) δ 1.28–1.40 (3H, m), 1.67–1.77 (4H,m), 1.96–2.07 (4H, m), 2.53–2.57 (2H, m), 2.76–2.84 (4H, m), 2.90–3.00(4H, m), 3.55 (2H, s), 3.74 (2H, t, J=6 Hz), 7.07–7.25 (4H, m), 7.73(2H, s). IR (KBr) νcm⁻¹: 1717, 1673, 1603, 1343, 1152.

Example 2738-(3-{1-[2-(3-Fluorophenyl)ethyl]-4-piperidinyl}propanoyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-onehydrochloride.

Using8-[3-(4-piperidinyl)propanoyl]-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-oneobtained in Reference Example 174 and 2-(3-fluorophenyl)ethylmethanesulfonate according to the same method as that of Example 81, thetitle compound was obtained as pale yellow crystals having a meltingpoint of 214 to 215° C.

¹H NMR (free base; 400 MHz, CDCl₃) δ 1.29–1.40 (3H, m), 1.68–1.77 (4H,m), 1.97–2.07 (4H, m), 2.54–2.58 (2H, m), 2.78–2.84 (4H, m), 2.93–3.00(4H, m), 3.55 (2H, s), 3.74 (2H, t, J=6 Hz), 6.86–6.98 (3H, m),7.20–7.26 (1H, m), 7.73 (2H, s). IR (KBr) νcm⁻: 1717, 1673, 1604, 1342,1143.

Example 2748-{3-[1-(3-Phenylpropyl)-4-piperidinyl]propanoyl}-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-onehydrochloride

Using8-[3-(4-piperidinyl)propanoyl]-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-oneobtained in Reference Example 174 and (3-bromopropyl)benzene accordingto the same method as that of Example 81, the title compound wasobtained as pale yellow amorphous powders.

¹H NMR (free base; 400 MHz, CDCl₃) δ 1.25–1.40 (3H, m), 1.63–1.73 (4H,m), 1.80–1.92 (5H, m), 2.00–2.06 (2H, m), 2.35 (2H, t, J=7.6 Hz), 2.62(2H, t, J=7.6 Hz), 2.82 (2H, t, J=6 Hz),2.91–2.95 (3H, m), 3.55 (2H, s),3.74 (2H, t, J=6 Hz), 7.12–7.33 (5H, m), 7.73 (2H, s). IR (KBr) νcm⁻¹:1714, 1672, 1604, 1496, 1344, 1153.

Example 2758-(3-{1-[2-(2-Methylphenoxy)ethyl]-4-piperidinyl}propanoyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-onehydrochloride

Using8-[3-(4-piperidinyl)propanoyl]-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-oneobtained in Reference Example 174 and 1-(2-bromoethoxy)-2-methylbenzeneaccording to the same method as that of Example 81, the title compoundwas obtained as pale yellow amorphous powders.

¹H NMR (free base; 400 MHz, CDCl₃) δ 1.30–1.35 (3H, m), 1.67–1.75 (4H,m), 2.00–2.06 (2H, m), 2.14 (2H, t, J=11.0 Hz), 2.21 (3H, s), 2.80–2.84(4H, m), 2.94 (2H, t, J=7.4 Hz), 3.03 (2H, d, J=11 Hz), 3.55 (2H, s),3.74 (2H, t, J=6 Hz), 4.11 (2H, t, J=6 Hz), 6.80–6.87 (2H, m), 7.12–7.15(2H, m), 7.73 (2H, s). IR (KBr) νcm⁻¹: 1718, 1673, 1604, 1496, 1343,1244.

Example 2768-(3-{1-[2-(2-Ethoxyphenoxy)ethyl]-4-piperidinyl}propanoyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-onehydrochloride

Using8-[3-(4-piperidinyl)propanoyl]-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-oneobtained in Reference Example 174 and 1-(2-bromoethoxy)-2-ethoxybenzeneaccording to the same method as that of Example 81, the title compoundwas obtained as pale yellow amorphous powders.

¹H NMR (free base; 400 MHz, CDCl₃) δ 1.30–1.39 (3H, m), 1.43 (3H, t, J=7Hz), 1.67–1.75 (4H, m), 2.00–2.13 (4H, m), 2.81–2.84 (4H, m), 2.94 (2H,t, J=7.5 Hz), 3.03 (2H, d, J=11 Hz), 3.55 (2H, s), 3.74 (2H, t, J=6 Hz),4.07(2H, q, J=7 Hz), 4.11–4.15 (2H, m), 6.87–6.91 (4H, m), 7.73 (2H, s).IR (KBr) νcm⁻¹: 1717, 1672, 1604, 1499, 1342, 1253.

Example 2779-{3-[1-(2-Phenylethyl)-4-piperidinyl]propanoyl}-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-onehydrochloride

Using9-[3-(4-piperidinyl)propanoyl]-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-oneobtained in Reference Example 176 and (2-bromoethyl)benzene according tothe same method as that of Example 81, the title compound was obtainedas pale yellow amorphous powders.

¹H NMR (free base; 400 MHz, CDCl₃) δ 1.30–1.40 (3H, m), 1.68–1.77 (4H,m), 1.94–2.03 (4H, m), 2.56–2.69 (2H, m), 2.68 (2H, t, J=7 Hz),2.79–2.86 (4H, m), 2.94 (4H, t, J=7 Hz), 3.02 (2H, d, J=11 Hz),), 3.90(2H, t, J=6 Hz), 7.17–7.30 (5H, m), 7.62 (2H, d, J=5.4 Hz). IR (KBr)νcm⁻¹: 1674, 1604, 1360, 1158.

Example 2789-(3-{1-[2-(2-Methoxyphenyl)ethyl]-4-piperidinyl}propanoyl)-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-onehydrochloride

Using9-[3-(4-piperidinyl)propanoyl]-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-oneobtained in Reference Example 176 and 2-(2-methoxyphenyl)ethylmethanesulfonate according to the same method as that of Example 81, thetitle compound was obtained as pale yellow amorphous powders.

¹H NMR (free base; 400 MHz, CDCl₃) δ 1.30–1.40 (3H, m), 1.67–1.76 (4H,m), 1.94–2.03 (4H, m), 2.51–2.55 (2H, m), 2.68 (2H, t, J=7 Hz),2.81–2.86 (4H, m), 2.94 (4H, t, J=7 Hz), 3.03 (2H, d, J=11 Hz), 3.81(3H, s), 3.89 (2H, t, J=6 Hz), 6.83–6.89 (2H, m), 7.13–7.20 (2H, m),7.62 (2H, d, J=5 Hz). IR (KBr) νcm⁻¹: 1674, 1604, 1494, 1362, 1339,1243, 1168.

Example 2799-(3-{1-[2-(2-Chlorophenyl)ethyl]-4-piperidinyl}propanoyl)-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-onehydrochloride

Using9-[3-(4-piperidinyl)propanoyl]-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-oneobtained in Reference Example 176 and 2-(2-methoxyphenyl)ethylmethanesulfonate according to the same method as that of Example 81, thetitle compound was obtained as pale yellow amorphous powders.

¹H NMR (free base; 400 MHz, CDCl₃) δ 1.30–1.40 (3H, m), 1.68–1.78 (4H,m), 1.94–2.07 (4H, m), 2.55–2.59 (2H, m), 2.68 (2H, t, J=7 Hz), 2.84(2H, t, J=6 Hz), 2.96 (6H, t, J=7 Hz), 3.03 (2H, d, J=l1Hz),3.89(2H, d,J=6 Hz), 7.12–7.34 (4H, m), 7.62 (2H, d, J=5 Hz). IR (KBr) νcm⁻¹: 1674,1604, 1489, 1361, 1339, 1168.

Example 2809-(3-{1-[2-(3-Methoxyphenyl)ethyl]-4-piperidinyl}propanoyl)-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-onehydrochloride

Using9-[3-(4-piperidinyl)propanoyl]-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-oneobtained in Reference Example 176and 2-(3-methoxyphenyl)ethylmethanesulfonate according to the same method as that of Example 81, thetitle compound was obtained as pale yellow amorphous powders.

¹H NMR (free base; 400 MHz, CDCl₃) δ 1.30–1.40 (3H, m), 1.67–1.77 (4H,m), 1.95–2.02 (4H, m), 2.53–2.60 (2H, m), 2.68 (2H, t, J=7 Hz),2.77–2.87 (4H, m), 2.92–3.02 (6H, m), 3.79 (3H, s), 3.89 (2H, t, J=6Hz), 6.73–6.80 (3H, m), 7.18–7.22 (1H, m), 7.62 (2H, d, J=5 Hz). IR(KBr) νcm⁻¹: 1674, 1603, 1485, 1361, 1339, 1167.

Example 2819-(3-{1-[2-(2-Methylphenyl)ethyl]-4-piperidinyl}propanoyl)-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-onehydrochloride

Using9-[3-(4-piperidinyl)propanoyl]-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-oneobtained in Reference Example 176 and 2-(3-methylphenyl)ethylmethanesulfonate according to the same method as that of Example 81, thetitle compound was obtained as pale yellow amorphous powders.

¹H NMR (free base; 400 MHz, CDCl₃) δ 1.30–1.40 (3H, m), 1.70–1.77 (4H,m), 1.94–2.02 (4H, m), 2.32 (3H, s), 2.54–2.58 (2H, m), 2.68 (2H, t, J=7Hz), 2.75–2.80 (2H, m), 2.83–2.86 (2H, m), 2.94 (4H, t, J=7 Hz), 3.02(2H, d, J=11 Hz), 3.89 (2H, t, J=6 Hz), 6.99–7.01 (3H, m), 7.17 (1H, t,J=7 Hz), 7.62 (2H, d, J=5 Hz). IR (KBr) νcm⁻¹: 1675, 1604, 1485, 1361,1339, 1166.

Example 2829-(3-{1-[2-(3-Chlorophenyl)ethyl]-4-piperidinyl}propanoyl)-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-onehydrochloride

Using9-[3-(4-piperidinyl)propanoyl]-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-oneobtained in Reference Example 176 and 2-(3-chlorophenyl)ethylmethanesulfonate according to the same method as that of Example 81, thetitle compound was obtained as pale yellow amorphous powders.

¹H NMR (free base; 400 MHz, CDCl₃) δ 1.30–1.40 (3H, m), 1.68–1.77 (4H,m), 1.94–2.02 (4H, m), 2.54–2.58 (2H, m), 2.68 (2H, t, J=7 Hz),2.76–2.80 (2H, m), 2.84 (2H, t, J=6 Hz), 2.90–3.00 (6H, m), 3.90 (2H, t,J=6 Hz), 7.08 (1H, d, J=7 Hz), 7.16–7.23 (3H, m), 7.62 (2H, d, J=5 Hz).IR (KBr) νcm⁻¹: 1674, 1603, 1483, 1360, 1338, 1167.

Example 2839-(3-{1-[2-(3-Fluorophenyl)ethyl]-4-piperidinyl}propanoyl)-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-onehydrochloride

Using9-[3-(4-piperidinyl)propanoyl]-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-oneobtained in Reference Example 176 and 2-(3-fluorophenyl)ethylmethanesulfonate according to the same method as that of Example 81, thetitle compound was obtained as pale yellow amorphous powders.

¹H NMR (free base; 400 MHz, CDCl₃) δ 1.30–1.40 (3H, m), 1.68–1.81 (4H,m), 1.94–2.02 (4H, m), 2.55–2.59 (2H, m), 2.68 (2H, t, J=7 Hz),2.78–2.86 (4H, m), 2.92–3.00 (6H, m), 3.89 (2H, t, J=6 Hz), 6.86–6.98(3H, m), 7.23 (1H, q, J=4 Hz), 7.62 (2H, d, J=5 Hz). IR (KBr) νcm⁻¹:1674, 1604, 1585, 1486, 1361, 1339, 1158.

Example 284(±)-9-{3-[1-(1-Methyl-2-phenylethyl)-4-piperidinyl]propanoyl}-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-onehydrochloride

Using9-[3-(4-piperidinyl)propanoyl]-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-oneobtained in Reference Example 176 and (±)-1-methyl-2-phenylethylmethanesulfonate according to the same method as that of Example 81, thetitle compound was obtained as pale yellow amorphous powders.

¹H NMR (free base; 400 MHz, CDCl₃) δ 0.94 (3H, d, J=6 Hz), 1.30–1.40(3H, m), 1.67–1.78 (4H, m), 1.94–2.00 (2H, m), 2.26–2.42 (2H, m), 2.68(2H, t, J=7 Hz), 2.84 (2H, t, J=6 Hz), 2.90–3.04 (9H, m), 3.90 (2H, t,J=6 Hz), 7.16–7.34 (5H, m), 7.62 (2H, d, J=5 Hz). IR (KBr) νcm⁻¹: 1673,1604, 1484, 1361, 1339, 1158.

Example 285(±)-9-(3-{1-[2-(2-Methoxyphenyl)-1-methylethyl]-4-piperidinyl}propanoyl)-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-onehydrochloride

Using9-[3-(4-piperidinyl)propanoyl]-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-oneobtained in Reference Example 176 and(±)-2-(2-methoxyphenyl)-1-methylethyl methanesulfonate according to thesame method as that of Example 81, the title compound was obtained aspale yellow amorphous powders.

¹H NMR (free base; 400 MHz, CDCl₃) δ 0.94 (3H, d, J=6 Hz), 1.30–1.40(3H, m), 1.67–1.77 (4H, m), 1.94–2.00 (2H, m), 2.36–2.44 (2H, m), 2.68(2H, t, J=7 Hz), 2.84 (2H, t, J=6 Hz), 2.92–3.04 (9H, m), 3.80 (3H, s),3.89 (2H, t, J=6 Hz), 6.83 (1H, d, J=7 Hz), 6.88 (1H, t, J=6 Hz), 7.10(1H, d, J=7 Hz), 7.17 (1H, t, J=6 Hz), 7.62 (2H, d, J=5 Hz). IR (KBr)νcm⁻¹: 1675, 1604, 1494, 1362, 1339, 1244, 1159.

Example 2869-{3-[1-(3-Phenylpropyl)-4-piperidinyl]propanoyl}-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-onehydrochloride

Using9-[3-(4-piperidinyl)propanoyl]-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-oneobtained in Reference Example 176 and (3-bromopropyl)benzene accordingto the same method as that of Example 81, the title compound wasobtained as pale yellow amorphous powders.

¹H NMR (free base; 400 MHz, CDCl₃) δ 1.28–1.40 (3H, m), 1.67–1.73 (4H,m), 1.79–1.91 (4H, m), 1.93–2.04 (2H, m), 2.35 (2H, t, J=7.5 Hz),2.60–2.70 (4H, m), 2.84 (2H, t, J=6 Hz), 2.90–2.95 (6H, m), 3.89 (2H, t,J=6 Hz), 7.15–7.29 (5H, m), 7.61 (2H, d, J=5 Hz). IR (KBr) νcm⁻¹: 1675,1604, 1361, 1339, 1166.

Example 287(±)-9-{3-[1-(1-Methyl-2-phenoxyethyl)-4-piperidinyl]propanoyl}-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-onehydrochloride

Using9-[3-(4-piperidinyl)propanoyl]-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-oneobtained in Reference Example 176 and (±)-(2-bromopropoxy)benzeneaccording to the same method as that of Example 81, the title compoundwas obtained as pale yellow amorphous powders.

¹H NMR (free base; 400 MHz, CDCl₃) δ 1.19 (3H, d, J=6 Hz), 1.30–1.40(3H, m), 1.66–1.76 (4H, m), 1.93–1.99 (2H, m), 2.28–2.40 (2H, m), 2.68(2H, t, J=7 Hz), 2.84 (2H, t, J=6 Hz), 2.91–3.04 (7H, m), 3.89 (2H, d,J=6 Hz), 4.05–4.10 (2H, m), 6.88–6.95 (3H, m), 7.25–7.30 (2H, m), 7.61(2H, d, J=5 Hz). IR (KBr) νcm⁻¹: 1674, 1601, 1496, 1361, 1339, 1244,1159.

Example 288(±)-9-(3-{1-[2-(2-Methoxyphenoxy)-1-methylethyl]-4-piperidinyl}propanoyl)-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-onehydrochloride

Using9-[3-(4-piperidinyl)propanoyl]-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-oneobtained in Reference Example 176 and(±)-1-((2-bromopropoxy)-2-methoxybenzene according to the same method asthat of Example 81, the title compound was obtained as pale yellowamorphous powders.

¹H NMR (free base; 400 MHz, CDCl₃) δ 1.18 (3H, d, J=6 Hz), 1.30–1.40(3H, m), 1.66–1.75 (4H, m), 1.94–2.00 (2H, m), 2.23–2.39 (2H, m), 2.68(2H, t, J=7 Hz), 2.84 (2H, t, J=6 Hz), 2.90–2.96 (6H, m), 3.07–3.11 (1H,m), 3.85 (3H, s), 3.89 (2H, d, J=6 Hz), 4.11–4.16 (2H, m), 6.88–6.94(4H, m), 7.61 (2H, d, J=5 Hz). IR (KBr) νcm⁻¹: 1673, 1601, 1506, 1362,1338, 1253, 1158.

Example 2896-{5-[(2-Phenylethyl)amino]pentanoyl}-3,4-dihydro-2(1H)-quinazolinonehydrochloride

Using 6-(5-chloropentanoyl)-3,4-dihydro-2(1H)-quinazolinone obtained inReference Example 177 and 2-phenylethylamine according to the samemethod as those of Reference Example 19 and Example 1, the titlecompound was obtained as colorless crystals having a melting point of199 to 205° C. (dec).

¹H NMR (300 MHz, DMSO-d₆) δ 1.68–1.66 (4H, m), 2.99–2.94 (6H, m), 3.10(2H, m), 4.38 (2H, s), 6.86 (1H, d, J=9.0 Hz), 7.04 (1H,s), 7.28–7.25(3H, m), 7.34–7.32 (2H, m), 7.80–7.76 (2H, m), 9.02 (2H, s), 9.47 (1H,br.s). elementary analysis as C₂₁H₂₅N₃O₂.HCl calculation value: C,65.02; H, 6.76; N, 10.83. experimental value: C, 64.42; H, 6.58;N,10.80. MS m/z: 352 [M+H]⁺

Example 2906-(5-{[2-(2-Methoxyphenyl)ethyl]amino}pentanoyl)-3,4-dihydro-2(1H)-quinazolinonehydrochloride

Using 6-(5-chloropentanoyl)-3,4-dihydro-2(1H)-quinazolinone obtained inReference Example 177 and 2-(2-methoxyphenyl)ethylamine according to thesame method as those of Reference Example 19 and Example 1, the titlecompound was obtained as colorless crystals having a melting point of176 to 180° C. (dec).

¹H NMR (300 MHz, DMSO-d₆) δ 1.66 (4H, m), 3.03–2.95 (8H, m), 3.79 (3H,s), 4.37 (2H, s), 7.01–6.83 (4H, m), 7.27–7.16 (2H, m), 7.78–7.75 (2H,m), 8.87 (2H, br.s), 9.44 (1H, s). elementary analysis asC₂₂H₂₇N₃O₃.HCl.H₂O calculation value: C, 63.22; H, 6.75; N, 10.05.experimental value: C, 62.98; H, 6.62; N, 10.11. MS m/z: 382 [M+H]⁺

Example 2916-(5-{[2-(2-Chlorophenyl)ethyl]amino}pentanoyl)-3,4-dihydro-2(1H)-quinazolinonehydrochloride

Using 6-(5-chloropentanoyl)-3,4-dihydro-2(1H)-quinazolinone obtained inReference Example 177 and 2-(2-chlorophenyl)ethylamine according to thesame methods as those of Reference Example 19 and Example 1, the titlecompound was obtained as colorless crystals having a melting point of176 to 185° C. (dec).

¹H NMR (300 MHz, DMSO-d₆) δ 1.68 (4H, m), 3.11–2.96 (8H, m), 4.39 (2H,s), 6.86 (1H, d, J=8.1 Hz), 7.04 (1H, s), 7.49–7.28 (4H, m), 7.81–7.77(2H, m), 9.17 (2H, br.s), 9.47 (1H, s). elementary analysis asC₂₁H₂₄ClN₃O₂.HCl calculation value: C, 59.72; H, 5.97; N, 9.95.experimental value: C, 59.43; H, 5.69; N, 9.51. MS m/z: 386 [M+H]⁺

Example 2926-{5-[Methyl(2-phenylethyl)amino]pentanoyl}-3,4-dihydro-2(1H)-quinazolinonehydrochloride

Using 6-(5-chloropentanoyl)-3,4-dihydro-2(1H)-quinazolinone obtained inReference Example 177 and N-methyl-N-(2-phenylethyl)amine according tothe same method as that of Example 9, the title compound was obtained ascolorless crystals having a melting point of 164 to 166° C.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.53–1.74 (4H, m), 2.30 (3H, s),2.42–2.47 (2H, m), 2.57–2.63 (2H, m), 2.75–2.80 (2H, m), 2.89–2.93 (2H,m), 4.59 (2H, s), 5.50 (1H, s), 6.76 (1H, d, J=8.1 Hz), 7.30–7.18 (5H,m), 7.70 (1H, s), 7.78 (1H, dd, J=8.1, 1.8 Hz), 8.34 (1H, s). elementaryanalysis as C₂₂H₂₇N₃O₂.HCl calculation value: C, 62.92; H, 7.20; N,10.01. experimental value: C, 62.59; H, 7.12; N, 10.13. MS m/z: 386[M+H]⁺

Example 2936-{5-[[2-(2-Methoxyphenyl)ethyl](methyl)amino]pentanoyl}-3,4-dihydro-2(1H)-quinazolinonehydrochloride

Using 6-(5-chloropentanoyl)-3,4-dihydro-2(1H)-quinazolinone obtained inReference Example 177 and N-[2-(2-methoxyphenyl)ethyl]-N-methylamineaccording to the same method as that of Example 9, the title compoundwas obtained as colorless crystals having a melting point of 170 to 171°C. (dec).

¹H NMR (300 MHz, DMSO-d₆) δ 1.79–1.63 (4H, m), 2.79 (3H, d, J=4.8 Hz),3.02–2.95 (4H, m), 3.24–3.07 (4H, m), 3.80 (3H, s), 4.38 (2H, m),6.94–6.84 (2H, m), 7.04–6.99 (2H, m), 7.30–7.20 (2H, m), 7.80–7.77 (2H,m), 9.47 (1H, s), 10.29 (1H, br.s). elementary analysis asC₂₃H₂₉N₃O₃.HCl.1.5H₂O calculation value: C, 60.19; H, 7.25; N, 9.16.experimental value: C, 60.69; H, 7.17; N, 9.38. MS m/z: 396 [M+H]⁺

Example 2946-{5-[[2-(2-Chlorophenyl)ethyl](methyl)amino]pentanoyl}-3,4-dihydro-2(1H)-quinazolinonehydrochloride

Using 6-(5-chloropentanoyl)-3,4-dihydro-2(1H)-quinazolinone obtained inReference Example 177 and N-[2-(2-chlorophenyl)ethyl]-N-methylamineaccording to the same method as that of Example 9, the title compoundwas obtained as colorless crystals having a melting point of 192 to 195°C. (dec).

¹H NMR (300 MHz, DMSO-d₆) δ 1.79–1.64 (4H, m), 2.82 (3H, d, J=4.8 Hz),3.02–2.97 (2H, m), 3.26–3.10 (6H, m), 4.38 (2H, s), 6.85 (1H, d, J=8.1Hz), 7.04 (1H, s), 7.38–7.30 (2H, m), 7.49–7.44 (2H, m), 7.80–7.76 (2H,m), 9.47 (1H, s), 10.73 (1H, br.s). elementary analysis as C₂₂H_(26ClN)₃O₂.HCl.0.5H₂O calculation value: C, 59.33; H, 6.34; N, 9.43.experimental value: C, 59.22; H, 6.77; N, 9.58. MS m/z: 400 [M+H]⁺

Example 2951,3-Dimethyl-6-{5-[methyl(2-phenylethyl)amino]pentanoyl}-3,4-dihydro-2(1H)-quinazolinonehydrochloride

Using 6-(5-chloropentanoyl)-1,3-dimethyl-3,4-dihydro-2(1H)-quinazolinoneobtained in Reference Example 178 and N-methyl-N-(2-phenylethyl)amineaccording to the same method as that of Example 9, the title compoundwas obtained as colorless crystals having a melting point of 174 to 176°C.

¹H NMR (300 MHz, DMSO-d₆) δ 1.79–1.62 (4H, m), 2.79 (3H, d, J=4.8 Hz),2.92 (3H, s), 3.07–3.02 (4H, m), 3.24 (3H,s), 3.41–3.13 (4H, m), 4.45(2H, s), 7.03 (1H, d, J=8.7 Hz), 7.38–7.24 (5H, m), 7.79 (1H, d, J=1.8Hz), 7.92 (1H, dd, J=8.7, 2.1 Hz), 10.58 (1H, br.s). elementary analysisas C₂₄H₃₁N₃O₂.HCl calculation value: C, 67.04; H, 7.50; N, 9.77.experimental value: C, 66.42; H, 7.67; N, 9.87. MS m/z: 394 [M+H]⁺

Example 2966-{5-[[2-(2-Methoxyphenyl)ethyl](methyl)amino]pentanoyl}-1,3-dimethyl-3,4-dihydro-2(1H)-quinazolinonehydrochloride

Using 6-(5-chloropentanoyl)-1,3-dimethyl-3,4-dihydro-2(1H)-quinazolinoneobtained in Reference Example 178 andN-[2-(2-methoxyphenyl)ethyl]-N-methylamine according to the same methodas that of Example 9, the title compound was obtained as colorlesscrystals having a melting point of 145 to 146° C.

¹H NMR (300 MHz, DMSO-d₆) δ 1.79–1.65 (4H, m), 2.78 (3H, s), 2.92 (3H,s), 3.18–2.96 (8H, m), 3.24 (3H, s), 3.81 (3H, s), 4.45 (2H, s),6.94–6.89 (1H, m), 7.04–6.99 (2H, m), 7.30–7.21 (2H, m), 7.79 (1H, d,J=1.8 Hz), 7.92 (1H, dd, J=8.6, 2.0 Hz), 10.57 (1H, br.s). elementaryanalysis as C₂₅H₃₃N₃O₃.HCl calculation value: C, 65.27; H, 7.45; N,9.13. experimental value: C, 64.68; H, 7.58; N, 9.31. MS m/z: 424 [M+H]⁺

Example 2976-{5-[[2-(2-Chlorophenyl)ethyl](methyl)amino]pentanoyl}-1,3-dimethyl-3,4-dihydro-2(1H)-quinazolinonehydrochloride

Using 6-(5-chloropentanoyl)-1,3-dimethyl-3,4-dihydro-2(1H)-quinazolinoneobtained in Reference Example 178 and 2-(2-chlorophenyl)ethylamineaccording to the same method as that of Example 9, the title compoundwas obtained as colorless crystals having a melting point of 187 to 188°C.

¹H NMR (300 MHz, DMSO-d₆) δ 1.77–1.66 (4H, m), 2.82 (3H, s), 2.92 (3H,s), 3.07–3.02 (2H, m), 3.24 (3H, s), 3.40–3.00 (6H, m), 4.44 (2H,s),7.03 (1H, d, J=8.4 Hz), 7.37–7.30 (2H, m), 7.49–7.44 (2H, m), 7.79 (1H,s), 7.91 (1H, d, J=8.4 Hz), 10.63 (1H, br.s). elementary analysis asC₂₄H₃₀ClN₃O₂.HCl.2H₂O calculation value: C, 61.99; H, 7.59; N, 9.04.experimental value: C, 61.97; H, 6.91; N, 9.31. MS m/z: 428 [M+H]⁺

Example 2988-[4-(Benzylamino)butanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using tert-butyl benzyl(4-oxo-4-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)butyl)carbamate(526 mg) obtained in Reference Example 180 according to the same methodas that of Example 1, the title compound (384 mg) was obtained ascolorless crystals having a melting point of 159 to 161° C.

¹H NMR (200 MHz, DMSO-d₆) δ 2.01 (2H, t, J=7.4 Hz), 2.59 (2H, t, J=7.6Hz), 2.80–3.25 (8H, m), 3.99 (2H, t, J=8.4 Hz), 4.05–4.20 (2H, m),7.35–7.65 (5H, m), 7.72 (2H, s), 9.40–9.60 (2H, br).

Example 2998-(4-{[2-(2-Methoxyphenyl)ethyl]amino}butanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using tert-butyl2-(2-methoxyphenyl)ethyl[4-oxo-4-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)butyl]carbamate(790 mg) obtained in Reference Example 181 according to the same methodas that of Example 1, the title compound (452 mg) was obtained ascolorless crystals having a melting point of 165 to 167° C.

¹H NMR (200 MHz, DMSO-d₆) δ 1.85–2.10 (2H, m), 2.60 (2H, t, J=7.6 Hz),2.90–3.25 (12H, m), 3.81 (3H, s), 4.00 (2H, t, J=8.4 Hz), 6.92 (1H, dt,J=7.3, 1.2 Hz), 7.00 (1H, d, J=7.3 Hz), 7.15–7.30 (2H, m), 7.74 (2H, s),9.00–9.20 (2H, br). elementary analysis as C₂₄H₂₉ClN₂O₃.0.5H₂Ocalculation value: C, 65.82; H, 6.90; N, 6.40. experimental value: C,65.37; H, 6.68; N, 6.34.

Example 3008-[5-(Benzylamino)pentanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using tert-butylbenzyl[5-oxo-5-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)pentyl]carbamate(498 mg) obtained in Reference Example 182 according to the same methodas that of Example 1, the title compound (340 mg) was obtained ascolorless crystals having a melting point of 123 to 125° C.

¹H NMR (200 MHz, DMSO-d₆) δ 1.55–1.85 (4H, m), 2.59 (2H, t, J=7.6 Hz),2.80–3.05 (6H, m), 3.17 (2H, t, J=8.4 Hz), 3.99 (2H, t, J=8.4 Hz),4.05–4.20 (2H, m), 7.35–7.65 (5H, m), 7.73 (2H, s), 9.40–9.60 (2H, br).

Example 3018-{5-((2-Methoxybenzyl)amino]pentanoyl}-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using tert-butyl2-methoxybenzyl[5-oxo-5-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)pentyl]carbamate(524 mg) obtained in Reference Example 183 according to the same methodas that of Example 1, the title compound (381 mg) was obtained ascolorless crystals having a melting point of 90 to 92° C.

¹H NMR (200 MHz, DMSO-d₆) δ 1.55–1.80 (4H, m), 2.60 (2H, t, J=7.6 Hz),2.80–3.05 (6H, m), 3.18 (2H, t, J=8.4 Hz), 3.75–4.10 (4H, m), 3.84 (3H,s), 6.95–7.15 (2H, m), 7.35–7.50 (2H, m), 7.73 (2H, s), 8.90–9.10 (2H,br).

Example 3028-[6-(Benzylamino)hexanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using tert-butyl benzyl[6-oxo-6-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)hexyl]carbamate(554 mg) obtained in Reference Example 184 according to the same methodas that of Example 1, the title compound (360 mg) was obtained ascolorless crystals having a melting point of 181 to 183° C.

¹H NMR (300 MHz, DMSO-d₆) δ 1.30–1.45 (2H, m), 1.55–1.80 (4H, m), 2.59(2H, t, J=7.5 Hz), 2.80–3.00 (6H, m), 3.17 (2H, t, J=8.4 Hz), 3.98 (2H,t, J=8.4 Hz), 4.05–4.20 (2H, m), 7.35–7.65 (5H, m), 7.72 (2H, s),9.35–9.55 (2H, br). elementary analysis as C₂₄H₂₉ClN₂O₂.1.5H₂Ocalculation value: C, 65.52; H, 7.33; N, 6.37. experimental value: C,65.53; H, 7.25; N, 6.17.

Example 3038-{6-[(2-Methoxybenzyl)amino]hexanoyl}-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using tert-butyl2-methoxybenzyl[6-oxo-6-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)hexyl]carbamate(486 mg) obtained in Reference Example 185 according to the same methodas that of Example 1, the title compound (393 mg) was obtained as paleyellow amorphous powders was obtained.

¹H NMR (300 MHz, DMSO-d₆) δ 1.30–1.45 (2H, m), 1.55–1.80 (4H, m), 2.59(2H, t, J=7.5 Hz), 2.90–3.00 (4H, m), 3.16 (2H, t, J=8.4 Hz), 3.84 (3H,s), 3.90–4.15 (6H, m), 6.99 (1H, t, J=7.5 Hz), 7.09 (1H, d, J=8.0 Hz),7.41 (1H, t, J=8.0 Hz), 7.51 (1H, d, J=7.5 Hz), 7.73 (2H, s), 9.00–9.20(2H, br).

Example 3046-{6-[(2-Phenylethyl)amino]hexanoyl}-2H-1,4-benzoxazin-3(4H)-onehydrochloride

Using tert-butyl6-oxo-6-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)hexyl(2-phenylethyl)carbamate(842 mg) obtained in Reference Example 186 according to the same methodas that of Example 1, the title compound (490 mg) was obtained ascolorless crystals having a melting point of 208 to 210° C.

¹H NMR (300 MHz, DMSO-d₆) δ 1.30–1.45 (2H, m), 1.55–1.70 (4H, m),2.85–3.00 (6H, m), 3.05–3.20 (2H, m), 4.68 (2H, s), 7.05 (1H, d, J=8.4Hz), 7.10–7.20 (5H, m), 7.51 (1H, s), 7.62 (1H, dd, J=8.4, 2.1 Hz),8.80–9.05 (2H, br), 10.91 (1H, s).

Example 3056-(6-{[2-(2-Methoxyphenyl)ethyl]amino}hexanoyl)-2H-1,4-benzoxazin-3(4H)-onehydrochloride

Using tert-butyl2-(2-methoxyphenyl)ethyl[6-oxo-6-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)hexyl]carbamate(974 mg) obtained in Reference Example 187 according to the same methodas that of Example 1, the title compound (567 mg) was obtained ascolorless crystals having a melting point of 151 to 153° C.

¹H NMR (300 MHz, DMSO-d₆) δ 1.30–1.45 (2H, m), 1.55–1.75 (4H, m),2.80–3.10 (8H, m), 3.80 (3H, s), 4.68 (2H, s), 6.91 (1H, t, J=7.5 Hz),7.00 (1H, d, J=7.8 Hz), 7.05 (1H, d, J=8.6 Hz), 7.19 (1H, d, J=7.5 Hz),7.26 (1H, dt, J=7.8, 1.8 Hz), 7.53 (1H, t, J=1.8 Hz), 7.62 .(1H, dd,J=8.6, 1.8 Hz), 8.90–9.10 (2H, br), 10.94 (1H, s).

Example 3066-(6-{[2-(2-Chlorophenyl)ethyl]amino}hexanoyl)-2H-1,4-benzoxazin-3(4H)-onehydrochloride

Using tert-butyl2-(2-chlorophenyl)ethyl[6-oxo-6-(3-oxo-3,4-dihydro-2H-1,4-benzooxazin-6-yl]hexyl]carbamate(974 mg) obtained in Reference Example 188 according to the same methodas that of Example 1, the title compound (387 mg) was obtained ascolorless crystals having a melting point of 183 to 185° C.

¹H NMR (300 MHz, DMSO-d₆) δ 1.30–1.45 (2H, m), 1.55–1.75 (4H, m),2.85–3.20 (8H, m), 4.68 (2H, s), 7.05 (1H, d, J=8.7 Hz), 7.25–7.55 (5H,m), 7.62 (1H, dd, J=8.4, 1.8 Hz), 8.80–9.20 (2H, br), 10.92 (1H, s).

Example 3078-{4-[(2-Phenylethyl)amino]butanoyl}-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using8-(4-chlorobutanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(1.00 g) obtained in Reference Example 179 and 2-phenylethylamine (870,mg) according to the same methods as those of Reference Example 19 andExample 1, the title compound (500 mg was obtained as colorlesscrystals.

¹H NMR (300 MHz, DMSO-d₆) δ 1.90–2.05 (2H, m), 2.60 (2H, t, J=7.6 Hz),2.90–3.25 (12H, m), 3.99 (2H, t, J=8.4 Hz), 7.20–7.40 (5H, m), 7.74 (2H,s), 9.00–9.20 (2H, br).

Example 3088-[5-(3,4-Dihydro-2(1H)-isoquinolinyl)pentanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using8-(5-chloropentanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(1.00 g) obtained in Reference Example 1 and1,2,3,4-tetrahydroisoquinoline (457 mg) according to the same method asthat of Example 9, the title compound (779 mg) was obtained as colorlesscrystals having a melting point of 203 to 205° C.

¹H NMR (free base; 300 MHz, CDCl₃) δ 1.60–1.90 (4H, m), 2.55 (2H, t,J=7.2 Hz), 2.60–2.80 (4H, m), 2.88, (2H, t, J=5.7 Hz), 2.90–3.00 (4H,m), 3.17 (2H, t, J=8.4 Hz), 3.61 (2H, s), 4.10 (2H, t, J=8.4 Hz),6.95–7.15 (4H, m), 7.67 (1H, s) 7.71, (1H, s).

Example 3098-(3-{1-[2-(2-Methoxyphenyl)ethyl]-4-piperidinyl}propanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using8-[3-(4-piperidinyl)propanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(1.50 g) and 2-(2-methoxyphenyl)ethyl methanesulfonate (1.16 g)according to the same method as that of Example 81, the title compound(1.69 g) was obtained as colorless crystals having a melting point of209 to 211° C.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.20–1.50 (3H, m), 1.60–2.10 (6H,m), 2.40–3.10 (12H, m), 3.23 (2H, t, J=8.4 Hz), 3.81 (3H, s), 4.13 (2H,t, J=8.4 Hz), 6.80–6.95 (2H, m), 7.10–7.25 (2H, m), 7.68 (1H, s), 7.72(1H, s). elementary analysis as C₂₈H₃₄N₂O₃.HCl.0.5H₂O calculation value:C, 68.35; H, 7.37; N, 5.69. experimental value: C, 68.85; H, 7.54; N,5.84.

Example 3108-(3-{1-[2-(3-Methoxyphenyl)ethyl]-4-piperidinyl}propanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using8-[3-(4-piperidinyl)propanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(1.50 g) and 2-(3-methoxyphenyl)ethyl methanesulfonate (1.16 g)according to the same method as that of Example 81, the title compound(1.53 g) was obtained as colorless crystals having a melting point of240 to 242° C.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.20–1.45 (3H, m), 1.55–2.10 (6H,m), 2.50–3.10 (12H, m), 3.23 (2H, t, J=8.4 Hz), 3.79 (3H, s), 4.14 (2H,t, J=8.4 Hz), 6.70–6.85 (3H, m), 7.15–7.30 (1H, m), 7.68 (1H, s), 7.72(1H, s). elementary analysis as C₂₈H₃₄N₂O₃.HCl.0.5H₂O calculation value:C, 68.35; H, 7.37; N, 5.69. experimental value: C, 68.92; H, 6.69; N,5.87.

Example 3118-(3-{1-[2-(4-Methoxyphenyl)ethyl]-4-piperidinyl}propanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using8-[3-(4-piperidinyl)propanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-oneand 2-(4-methoxyphenyl)ethyl methanesulfonate according to the samemethod as that of Example 81, the title compound was obtained ascolorless crystals having a melting point of 141 to 143° C.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.30–1.60 (3H, m), 1.65–1.85 (4H,m), 2.00–2.20 (2H, m), 2.60–3.15 (12H, m), 3.23 (2H, t, J=8.4 Hz), 3.78(3H, s), 4.14 (2H, t, J=8.4 Hz), 6.83 (2H, d, J=8.6 Hz), 7.13 (2H, d,J=8.6 Hz), 7.67 (1H, s), 7.72 (1H, s). elementary analysis asC₂₈H₃₄N₂O₃.HCl.H₂O calculation value: C, 67.12; H, 7.44; N, 5.59.experimental value: C, 67.29; H, 7.56; N, 5.32.

Example 3128-(3-{1-[2-(2-Ethoxyphenyl)ethyl]-4-piperidinyl}propanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using8-[3-(4-piperidinyl)propanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-oneand 2-(2-ethoxyphenyl)ethyl methanesulfonate according to the samemethod as that of Example 81, the title compound was obtained ascolorless crystals having a melting point of 182 to 184° C.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.30–1.50 (3H, m), 1.41 (3H, t,J=7.0 Hz), 1.65–1.85 (4H, m), 1.95–2.10 (2H, m), 2.50–2.65 (2H, m), 2.71(2H, t, J=7.6 Hz), 2.80–3.15 (8H, m), 3.23 (2H, t, J=8.4 Hz), 4.03 (2H,q, J=7.0 Hz), 4.14 (2H, t, J=8.4 Hz), 6.75–6.90 (2H, m), 7.10–7.20 (2H,m), 7.68 (1H, s), 7.72 (1H, s). elementary analysis asC₂₉H₃₆N₂O₃.HCl.H₂O calculation value: C, 67.62; H, 7.63; N, 5.44.experimental value: C, 67.08; H, 7.24; N, 5.28.

Example 3138-(3-{1-[2-(2-Hydroxyphenyl)ethyl]-4-piperidinyl}propanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

A solution of8-(3-{1-[2-(2-methoxyphenyl)ethyl]-4-piperidinyl}propanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(800 mg obtained in Example 309 in hydrobromic acid (15 ml) was, stirredat 140° C. for 1 hour. A pH of the reaction solution was adjusted to 12with an aqueous potassium carbonate solution, and the solution wasextracted with ethyl acetate. The extract was washed with brine, driedover anhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure to give a free base compound (622 mg) of the titlecompound as colorless crystals having a melting point of 143 to 145° C.The free base compound (500 mg) was treated with a hydrogenchloride-ethanol solution to give the title compound (432 mg) ascolorless crystals having an melting point of 220 to 222° C.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.25–1.50 (3H, m), 1.65–1.90 (4H,m), 2.05–2.20 (2H, m), 2.60–2.70 (2H, m), 2.72 (2H, t, J=7.8 Hz),2.75–2.85 (3H, m), 2.94 (2H, t, J=7.8 Hz), 3.03 (2H, t, J=7.8 Hz),3.10–3.20 (2H, m), 3.26 (2H, t, J=8.5 Hz), 4.14 (2H, t, J=8.5 Hz), 6.73(1H, dt, J=7.3, 1.2 Hz), 6.87 (1H, dd, J=5.2, 0.8 Hz), 6.98 (1H, dd,J=4.8, 0.8 Hz), 7.12 (1H, dt, J=7.9, 1.5 Hz), 7.67 (1H, s), 7.72 (1H,s). elementary analysis as C₂₇H₃₂N₂O₃.HCl.0.5H₂O calculation value: C,67.84; H, 7.17; N, 5.86. experimental value: C, 67.78; H, 7.51; N, 5.87.

Example 3148-(3-{1-[2-(3-Hydroxyphenyl)ethyl]-4-piperidinyl}propanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using8-(3-{1-[2-(3-methoxyphenyl)ethyl]-4-piperidinyl}propanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-oneobtained in Example 310 according to the same method as that of Example313, the title compound was obtained as colorless crystals having amelting point of 229 to 231° C.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.20–1.55 (3H, m), 1.60–1.85 (4H,m), 1.90–2.20 (2H, m), 2.55–3.15 (13H, m), 3.27 (2H, t, J=8.4 Hz), 4.14(2H, t, J=8.4 Hz), 6.60–6.75 (3H, m), 7.10–7.20 (1H, m), 7.67 (1H, s),7.72 (1H, s). elementary analysis as C₂₇H₃₂N₂O₃.HCl.0.5H₂O calculationvalue: C, 67.84; H, 7.17; N, 5.86. experimental value: C, 68.07; H,7.35; N, 5.69.

Example 3158-(3-{1-[2-(3-Methylphenyl)ethyl]-4-piperidinyl}propanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using8-[3-(4-piperidinyl)propanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(500 mg) and 2-(3-methylphenyl)ethyl methanesulfonate (360 mg) accordingto the same method as that of Example 81, the title compound (391 mg)was obtained as colorless crystals having a melting point of 197 to 199°C.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.25–1.50 (3H, m), 1.60–1.85 (4H,m), 1.90–2.10 (2H, m), 2.32 (3H, s), 2.45–3.10 (12H, m), 3.22 (2H, t,J=8.4 Hz), 4.13 (2H, t, J=8.4 Hz), 6.95–7.20 (4H, m), 7.68 (1H, s), 7.72(1H, s). elementary analysis as C₂₈H₃₄N₂O₂.HCl.0.5H₂O calculation value:C, 70.64; H, 7.62; N, 5.88. experimental value: C, 70.53; H, 7.52; N,5.91.

Example 3168-(3-{1-[2-(2-Chlorophenyl)ethyl]-4-piperidinyl}propanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using8-[3-(4-piperidinyl)propanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(600 mg and 2-(2-chlorophenyl)ethyl methanesulfonate (475 mg) accordingto the same method as that of Example 81, the title compound (303 mg)was obtained as colorless crystals having a melting point of 207 to 210°C.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.20–1.45 (3H, m), 1.60–1.80 (4H,m), 1.95–2.10 (2H, m), 2.50–2.60 (2H, m), 2.72 (2H, t, J=7.6 Hz),2.85–3.10 (8H, m), 3.23 (2H, t, J=8.4 Hz), 4.14 (2H, t, J=8.4 Hz),7.10–7.40 (4H, m), 7.68 (1H, s), 7.72 (1H, s). elementary analysis asC₂₇H₃₁ClN₂O₂.HCl.0.5H₂O calculation value: C, 65.32; H, 6.70; N, 5.64.experimental value: C, 65.77; H, 6.87; N, 5.63.

Example 3178-(3-{1-[2-(4-Chlorophenyl)ethyl]-4-piperidinyl}propanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using8-[3-(4-piperidinyl)propanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-oneand 2-(4-chlorophenyl)ethyl methanesulfonate according to the samemethod as that of Example 81, the title compound was obtained ascolorless crystals having a melting point of 204 to. 206° C.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.40–1.90 (7H, m), 2.10–2.30 (2H,m), 2.72 (2H, t, J=7.8 Hz), 2.85–3.30 (12H, m), 4.14 (2H, t, J=8.4 Hz),7.10–7.30 (4H, m), 7.67 (1H, s), 7.71 (1H, s). elementary analysis asC₂₇H₃₁ClN₂O₂.HCl.H₂O calculation value: C, 64.16; H, 6.78; N, 5.54.experimental value: C, 64.15; H, 7.04; N, 5.25.

Example 3188-(3-{1-[2-(4-Nitrophenyl)ethyl]-4-piperidinyl}propanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using8-[3-(4-piperidinyl)propanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(500 mg) and 1-(2-bromoethyl)-4-nitrobenzene (368 mg) according to thesame method as that of Example 81, the title compound (443 mg) wasobtained as colorless crystals having a melting point of 217 to 219° C.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.25–1.55 (3H, m), 1.60–1.85 (4H,m), 1.95–2.20 (2H, m), 2.60–2.75 (4H, m), 2.85–3.15 (8H, m), 3.23 (2H,t, J=8.4 Hz), 4.14 (2H, t, J=8.4 Hz), 7.37 (2H, d, J=8.6 Hz), 7.67 (1H,s), 7.72 (1H, s), 8.14 (2H, d, J=8.6 Hz). elementary analysis asC₂₇H₃₁N₃O₄.HCl.0.5H₂O calculation value: C, 63.96; H, 6.56; N, 8.29.experimental value: C, 63.67; H, 6.77; N, 8.25.

Example 3198-(3-{1-[2-(2,6-Dichlorophenyl)ethyl]-4-piperidinyl}propanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using8-[3-(4-piperidinyl)propanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(600 mg) and 2-(2,6-dichlorophenyl)ethyl methanesulfonate (545 mg)according to the same method as that of Example 81, the title compound(272 mg) was obtained as colorless crystals having a melting point of226 to 229° C.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.25–1.50 (3H, m), 1.60–1.80 (4H,m), 2.00–2.20 (2H, m), 2.50–2.60 (2H, m), 2.68 (2H, t, J=7.6 Hz),2.85–3.30 (10H, m), 4.14 (2H, t, J=8.4 Hz), 7.00–7.10 (1H, m), 7.20–7.30(2H, m), 7.68 (1H, s), 7.72 (1H, s). elementary analysis asC₂₇H₃₀Cl₂N₂O₂.HCl.0.5H₂O calculation value: C, 61.08; H, 6.08; N, 5.28.experimental value: C, 60.96; H, 6.32; N, 5.04.

Example 3208-(3-{1-[2-(1H-Indol-3-yl)ethyl]-4-piperidinyl}propanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one hydrochloride

Using8-[3-(4-piperidinyl)propanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(500 mg) and 3-(2-bromoethyl)-1H-indole (394 mg) according to the samemethod as that of Example 81, the title compound (370 mg) was obtainedas colorless crystals having a melting point of 157 to 159° C.

¹H NMR (free base; 300 MHz, CDCl₃) δ 1.25–1.50 (3H, m), 1.60–1.85 (4H,m), 1.95–2.10 (2H, m), 2.60–2.80 (4H, m), 2.85–3.15 (8H, m), 3.23 (2H,t, J=8.4 Hz), 4.14 (2H, t, J=8.4 Hz), 7.00–7.25 (3H, m), 7.36 (1H, d,J=8.1 Hz), 7.62 (1H, d, J=8.1 Hz), 7.68 (1H, s), 7.73 (1H, s), 8.00–8.25(1H, br). elementary analysis as C₂₉H₃₃N₃O₂.HCl.H₂O calculation value:C, 68.29; H, 7.11; N, 8.24. experimental value: C, 68.77; H, 7.44; N,7.94.

Example 321(±)-8-{3-[1-(1-Methyl-2-phenylethyl)-4-piperidinyl]propanoyl}-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using8-[3-(4-piperidinyl)propanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(700 mg) and (±)-1-methyl-2-phenylethyl methanesulfonate (528 mg)according to the same method as that of Example 81, the title compound(257 mg) was obtained as colorless crystals having a melting point of211 to 213° C.

¹H NMR (free base; 300 MHz, CDCl₃) δ 0.94 (3H, d, J=6.6 Hz), 1.20–1.45(3H, m), 1.60–1.85 (4H, m), 2.10–2.45 (3H, m), 2.60–3.10 (10H, m), 3.23(2H, t, J=8.4 Hz), 4.14 (2H, t, J=8.4 Hz), 7.10–7.40 (5H, m), 7.68 (1H,s), 7.72 (1H, s.). elementary analysis as C₂₈H₃₄N₂O₂.HCl.0.5H₂Ocalculation value: C, 70.64; H, 7.62; N, 5.88. experimental value: C,70.80; H, 7.59; N, 5.88.

Example 322(±)-8-(3-{1-[2-(2-Methoxyphenyl)-1-methylethyl]-4-piperidinyl}propanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using8-[3-(4-piperidinyl)propanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(600 mg) and (±)-2-(2-methoxyphenyl)-1-methylethyl methanesulfonate (516mg) according to the same method as that of Example 81, the titlecompound (204 mg) was obtained as pale yellow amorphous powders.

¹H NMR (free base; 300 MHz, CDCl₃) δ 0.93 (3H, d, J=6.6 Hz), 1.20–1.40(3H, m), 1.60–1.80 (4H, m), 2.20–2.45 (3H, m), 2.71 (2H, t, J=7.8 Hz),2.80–3.05 (8H, m), 3.22 (2H, t, J=8.4 Hz), 3.80 (3H, s), 4.12 (2H, t,J=8.4 Hz), 6.80–6.90 (2H, m), 7.05–7.20 (2H, m), 7.67 (1H, s), 7.71 (1H,s). elementary analysis as C₂₉H₃₆N₂O₃.HCl.H₂O calculation value: C,67.62; H, 7.63; N, 5.44. experimental value: C, 67.65; H, 7.52; N, 5.42.

Example 323(±)-8-{3-[1-(1-Methyl-2-phenoxyethyl)-4-piperidinyl]propanoyl}-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using8-[3-(4-piperidinyl)propanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(700 mg) and (±)-1-methyl-2-phenoxyethyl methanesulfonate (566 mg)according to the same method as that of Example 81, the title compound(559 mg) was obtained as pale yellow amorphous powders.

¹H NMR (free base; 300 MHz, CDCl₃) δ 1.19 (3H, d, J=6.6 Hz), 1.20–1.45(3H, m), 1.60–1.80 (4H, m), 2.00–2.50 (3H, m), 2.71 (2H, t, J=7.8 Hz),2.80–3.10 (6H, m), 3.22 (2H, t, J=8.4 Hz), 3.87 (1H, dd, J=9.4, 6.2 Hz),4.00–4.20 (3H, m), 6.80–7.00 (3H, m), 7.20–7.35 (2H, m), 7.67 (1H, s),7.71 (1H, s). elementary analysis as C₂₈H₃₄N₂O₃.HCl.0.5H₂O calculationvalue: C, 68.35; H, 7.37; N, 5.69. experimental value: C, 68.37; H,7.57; N, 5.63.

Example 324(±)-8-(3-{1-[2-(2-Methoxyphenoxy)-1-methylethyl]-4-piperidinyl}propanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onemethanesulfonate hydrochloride

Using8-[3-(4-piperidinyl)propanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(600 mg) and (±)-2-(2-methoxyphenoxy)-1-methylethyl methanesulfonate(550 mg) according to the same method as that of Example 81, the titlecompound (181 mg) was obtained as pale yellow amorphous powders.

¹H NMR (free base; 300 MHz, CDCl₃) δ 1.19 (3H, d, J=6.6 Hz), 1.20–1.40(3H, m), 1.60–1.80 (4H, m), 2.25–2.40 (2H, m), 2.72 (2H, t, J=7.8 Hz),2.85–3.15 (7H, m), 3.22 (2H, t, J=8.4 Hz), 3.80–3.90 (1H, m), 3.85 (3H,s), 4.10–4.20 (3H, m), 6.85–7.00 (4H, m), 7.67 (1H, s), 7.71 (1H, s).elementary analysis as C₂₉H₃₆N₂O₄.HCl.0.5H₂O calculation value: C,66.72; H, 7.34; N, 5.37. experimental value: C, 66.33; H, 7.54; N, 5.28.

Example 3258-{3-[1-(2-Oxo-2-phenylethyl)-4-piperidinyl]propanoyl}-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one hydrochloride

Using8-[3-(4-piperidinyl)propanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(500 mg) and phenacyl chloride (248 mg) according to the same method asthat of Example 81, the title compound (301 mg) was obtained ascolorless crystals having a melting point of 114 to 116° C.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.35–1.60 (3H, m), 1.65–1.85 (4H,m), 2.15–2.35 (2H, m), 2.72 (2H, t, J=7.6 Hz), 2.85–3.10 (6H, m), 3.23(2H, t, J=8.4 Hz), 3.86 (2H, s), 4.14 (2H, t, J=8.4 Hz), 7.40–7.75 (5H,m), 7.98 (1H, s), 8.02 (1H, s). elementary analysis as C₂₇H₃₀N₂O₃.HClcalculation value: C, 66.86; H, 6.86; N, 5.78. experimental value: C,66.64; H, 7.25; N, 5.36.

Example 326(±)-8-{3-[1-(2-Hydroxy-2-phenylethyl)-4-piperidinyl]propanoyl}-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

A mixture of8-[3-(4-piperidinyl)propanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(500 mg) and styrene oxide (193 mg) in tetrahydrofuran (1 ml) wasstirred at 100° C. for 1 hour. The reaction mixture was purified bysilica gel chromatography (eluting solvent; ethyl acetate-methanol(9:1)) to give a free base compound of the title compound as colorlesscrystals (468 mg) having a melting point of 133 to 135° C. The free basecompound (390 mg) was treated with a hydrogen chloride-ethanol solutionto give the title compound (405 mg) as colorless crystals having amelting point of 235 to 237° C.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.30–1.55 (3H, m), 1.60–1.85 (4H,m), 2.00–2.20 (1H, m), 2.25–2.45 (1H, m), 2.50–2.60 (2H, m), 2.72 (2H,t, J=7.6 Hz), 2.85–3.05 (5H, m), 3.15–3.30 (3H, m), 3.40–4.40 (1H, br.),4.14 (2H, t, J=8.4 Hz), 4.80 (1H, dd, J=8.4, 5.4 Hz), 7.20–7.40 (5H, m),7.68 (1H, s), 7.72 (1H, s). elementary analysis as C₂₇H₃₂N₂O₃.HCl.0.5H₂Ocalculation value: C, 67.84; H, 7.17; N, 5.86. experimental value: C,68.30; H, 7.47; N, 5.72.

Example 3271-(3-Amino-4-methoxyphenyl)-3-{1-[2-(2-ethoxyphenoxy)ethyl]-4-piperidinyl}-1-propanonedihydrochloride

1-(2-Bromoethoxy)-2-ethoxybenzene (732 mg) was added to a suspension of1-(3-amino-4-methoxyphenyl)-3-(4-piperidinyl)-1-propanonedihydrochloride (1.00 g) obtained in Reference Example 191 and potassiumcarbonate (1.00 g) in ethanol (20 ml) at room temperature. Afterstirring at 80° C. for 12 hours, the reaction mixture was concentratedunder reduced pressure. Water (30 ml) and ethyl acetate (40 ml) wereadded to the residue, and the mixture was extracted with ethyl acetate.The organic layer was washed with brine, dried over anhydrous magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theresulting residue was purified by silica gel chromatography (elutingsolvent; ethyl acetate-methanol (9:1)) to give a free base compound ofthe title compound as colorless crystals (828 mg) having a melting pointof 81 to 82° C. The free base compound (200 mg) was treated with ahydrogen chloride-ethanol solution to give the title compound (240 mg)as colorless crystals having a melting point of 123 to 125° C.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.20–1.45 (3H, m), 1.43 (3H, t,J=7.0 Hz), 1.60–1.80 (4H, m), 2.00–2.20 (2H, m), 2.50–4.50 (2H, br),2.83 (2H, t, J=6.2 Hz), 2.91 (2H, t, J=7.2 Hz), 2.95–3.10, (2H, m), 3.91(3H, s), 4.06 (2H, q, J=7.0 Hz), 4.16 (2H, t, J=6.2 Hz), 6.79 (1H, d,J=8.4 Hz), 6.85–6.95 (4H, m), 7.35–7.45 (2H, m). elementary analysis asC₂₅H₃₄N₂O₄.2HCl.H₂O calculation value: C, 58.02; H, 7.40; N, 5.41.experimental value: C, 57.66; H, 7.82; N, 4.99.

Example 328N-[5-(3-{1-[2-(2-Ethoxyphenoxy)ethyl]-4-piperidinyl}propanoyl)-2-methoxyphenyl]methanesulfonamidehydrochloride

Methanesulfonyl chloride (0.108 ml) was added to a solution of1-(3-amino-4-methoxyphenyl)-3-{1-[2-(2-ethoxyphenoxy)ethyl]-4-piperidinyl}-1-propanonedihydrochloride (300 mg) obtained in Example 327 and triethylamine(0.195 ml) in tetrahydrofuran (10 ml) at room temperature, the mixturewas stirred for 12 hours, and the reaction mixture was concentratedunder reduced pressure. Water (30 ml) and ethyl acetate (40 ml) wereadded to the residue, and the mixture was extracted with ethyl acetate.The organic layer was washed with brine, dried over anhydrous magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theresulting residue was purified by silica gel chromatography (elutingsolvent; ethyl acetate-methanol (9:1)) to give a free base compound ofthe title compound as a colorless oil (291 mg). The free base compound(290 mg) was treated with a hydrogen chloride-ethanol solution to givethe title compound (277 mg) as colorless amorphous powders.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.20–1.45 (3H, m), 1.43 (3H, t,J=7.0 Hz), 1.60–1.80 (4H, m), 2.05–2.20 (2H, m), 2.84 (2H, t, J=6.2 Hz),2.90–3.10 (2H, m), 2.99 (3H, s), 3.45 (3H, s), 3.95–4.20 (7H, m),6.85–6.95 (4H, m), 6.94 (1H, d, J=5.6 Hz), 7.82 (1H, dd, J=8.4, 2.2 Hz),8.11 (1H, d, J=2.2 Hz). elementary analysis as C₂₆H₃₆N₂O₆S.HCl.1.5H₂Ocalculation value: C, 54.97; H, 7.10; N, 4.93. experimental value: C,54.63; H, 6.93; N, 4.57.

Example 329 N-[5-(3-{1-[2-(2-Ethoxyphenoxy)ethyl]-4-piperidinyl}propanoyl)-2-methoxyphenyl]acetamide hydrochloride

Acetic acid anhydride (0.132 ml) was added to a solution of1-(3-amino-4-methoxyphenyl)-3-{1-[2-(2-ethoxyphenoxy)ethyl]-4-piperidinyl}-1-propanone dihydrochloride (300 mg) obtained inExample 327 and triethylamine (0.195 ml) in tetrahydrofuran (10 ml) atroom temperature, the mixture was stirred for 12 hours, and the reactionmixture was concentrated under reduced pressure. Water (30 ml) and ethylacetate (40 ml) were added to the residue, and extracted with ethylacetate. The organic layer was washed with brine, dried over anhydrousmagnesium sulfate, and the solvent was evaporated under reducedpressure. The resulting residue was purified by silica gelchromatography (eluting solvent; ethyl acetate-methanol (9:1)) to give afree base compound of the title compound as a colorless oil (276 mg),The free base compound (270 mg) was treated with a hydrogenchloride-ethanol solution to give the title compound (277 mg) ascolorless crystals having a melting point of 127 to 129° C.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.20–1.45 (3H, m), 1.43 (3H, t,J=7.0 Hz), 1.60–1.80 (4H, m), 2.05–2.20 (2H, m), 2.23 (3H, s), 2.83 (2H,t, J=6.2 Hz), 2.90–3.10 (4H, m), 3.94 (3H, s), 4.07 (2H, q, J=7.0 Hz),4.15 (2H, t, J=6.2 Hz), 6.80–7.00 (5H, m), 7.70–7.80 (2H, m), 9.01 (1H,s). elementary analysis as C₂₇H₃₆N₂O₅.HCl.0.5H₂O calculation value: C,63.09; H, 7.45; N, 5.45. experimental value: C, 60.19; H, 7.42; N, 5.22.

Example 330(±)-8-{3-[1-(2,3-Dihydro-1H-inden-1-yl)-4-piperidinyl]propanoyl}-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

1-Chloroindane (360 mg) was added to a suspension of8-[3-(4-piperidinyl)propanoyl]1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(700 mg), potassium carbonate (700 mg) and potassium iodide (catalyticamount) in acetonitrile (10 ml) at room temperature, the mixture wasstirred for 12 hours, and the reaction mixture was concentrated underreduced pressure. Water (15 ml) and ethyl acetate (20 ml) were added tothe residue, and extracted with ethyl acetate. The extract was washedwith brine, dried over anhydrous magnesium sulfate, and the solvent wasevaporated under reduced pressure. The resulting residue was purified bysilica gel chromatography (eluting solvent; ethyl acetate-methanol(9:1)) to give a free base compound of the title compound as colorlesscrystals (285 mg) having a melting point of 111 to 113° C. The free basecompound (270 mg) was treated with a hydrogen 20 chloride-ethanolsolution to give, the title compound (270 mg) as pale yellow amorphouspowders.

¹H NMR (free base;, 300 MHz, CDCl₃) δ 1.00–1.45 (3H, m), 1.60–1.80 (4H,m), 2.00–2.30 (4H, m), 2.60–2.95 (8H, m), 3.02 (2H, t, J=7.5 Hz), 3.22(2H, t, J=8.4 Hz), 4.13 (2H, t, J=8.4 Hz), 4.35 (1H, t, J=7.0 Hz),7.15–7.40 (3H, m), 7.60–7.80 (3H, m). elementary analysis asC₂₈H₃₂N₂O₂.HCl.2.0H₂O calculation value: C, 67.12; H, 7.44; N, 5.59.experimental value: C, 67.34; H, 7.30; N, 5.45.

Example 331(±)-8-{3-[1-(1,2,3,4-Tetrahydro-1-naphthalenyl)-4-piperidinyl]propanoyl}-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using8-[3-(4-piperidinyl)propanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(500 mg) and (±)-1-chloro-1,2,3,4-tetrahydronaphthalene (280 mg)according to the same method as that of Example 330, the title compound(43 mg) was obtained as pale yellow amorphous powders.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.10–1.45 (3H, m), 1.55–1.80 (6H,m), 1.85–2.10 (4H, m), 2.50–3.10 (10H, m), 3.23 (2H, t, J=8.4 Hz),3.75–3.85 (1H, m), 4.14 (2H, t, J=8.4 Hz), 7.00–7.20 (3H, m), 7.65–7.75(3H, m).

Example 332(±)-8-{3-[1-(1,2,3,4-Tetrahydro-2-naphthalenyl)-4-piperidinyl]propanoyl}-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using8-[3-(4-piperidinyl)propanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(600 mg) and (±)-1,2,3,4-tetrahydro-2-naphthalenyl methanesulfonate (456mg) according to the same method as that of Example 330, the titlecompound (290 mg) was obtained as colorless crystals having a meltingpoint of 223 to 225° C.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.20–1.45 (3H, m), 1.55–1.85 (4H,m), 2.00–2.40 (3H, m), 2.60–3.10 (14H, m), 3.23 (2H, t, J=8.4 Hz), 4.14(2H, t, J=8.4 Hz), 7.00–7.20 (4H, m), 7.68 (1H, s), 7.73 (1H, s).elementary analysis as C₂₉H₃₄N₂O₂.HCl.H₂O calculation value: C, 70.07;H, 7.50; N, 5.64. experimental value: C, 69.77; H, 7.26; N, 5.56.

Example 3338-{3-[1-(6,7,8,9-Tetrahydro-5H-benzo[a]cyclohepten-7-yl)-4-piperidinyl]propanoyl}-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using8-[3-(4-piperidinyl)propanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(60 mg) and 6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-7-ylmethanesulfonate (485 mg) according to the same method as that ofExample 330, the title compound (51 mg) was obtained as pale yellowamorphous powders.

¹H NMR (free base; 300 MHz, CDCl₃) δ 1.30–1.60 (5H, m), 1.60–1.85 (4H,m), 2.15–2.50 (4H, m), 2.65–2.95 (1H, m), 3.02 (2H, t, J=7.8 Hz), 3.22(2H, t, J=8.4 Hz), 4.13 (2H, t, J=8.4 Hz), 7.12 (4H, s), 7.67 (1H, s),7.71 (1H, s).

Example 334 8-{3-[2,3-Dihydro-1H-inden-2-yl(ethyl)amino]propanoyl}-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using8-(3-chloropropanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(489 mg) obtained in Reference Example 192 andN-(2,3-dihydro-1H-inden-2-yl)-N-ethylamine (330 mg) according to thesame method as that of Example 9, the title compound (406 mg) wasobtained as colorless crystals having a melting point of 192 to 196° C.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.10 (3H, t, J=7.2 Hz), 2.10–2.45(1H, m), 2.60–3.30 (16H, m), 3.55–3.75 (1H, m), 4.13 (2H, t, J=8.4 Hz),7.00–7.20 (4H, m), 7.68 (1H, s), 7.72 (1H, s).

Example 3358-[4-(1,3,4,5-Tetrahydro-2H-2-benzazepin-2-yl)butanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using8-(4-chlorobutanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(500 mg) obtained in Reference Example 179 and2,3,4,5-tetrahydro-1H-2-benzazepine (290 mg) according to the samemethod as that of Example 9, the title compound (538 mg) was obtained ascolorless crystals having a melting point of 230 to 232° C.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.60–1.80 (2H, m), 1.90 (2H,quintet, J=7.2 Hz), 2.40 (2H, t, J=7.2 Hz), 2.70 (2H, t, J=7.6 Hz),2.80–3.15 (8H, m), 3.20 (2H, t, J=8.4 Hz), 3.87 (2H, s), 4.12 (2H, t,J=8.4 Hz), 7.00–7.20 (4H, m), 7.66 (1H, s), 7.70 (1H, s). elementaryanalysis as C₂₅H₂₈N₂O₂.HCl calculation value: C, 70.66; H, 6.88; N,6.59. experimental value: C, 70.20; H, 6.80; N, 6.56.

Example 3368-[4-(7-Methoxy-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)butanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using8-(4-chlorobutanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(500 mg) obtained in Reference Example 179 and7-methoxy-2,3,4,5-tetrahydro-1H-2-benzazepine (320 mg) according to thesame method as that of Example 9, the title compound (246 mg) wasobtained as colorless crystals having a melting point of 121 to 123° C.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.65–1.80 (2H, m), 1.91 (2H,quintet, J=7.0 Hz), 2.42 (2H, t, J=7.0 Hz), 2.71 (2H, t, J=7.6 Hz),2.80–3.15 (8H, m), 3.21 (2H, t, J=8.4 Hz), 3.78 (3H, s), 3.84 (2H, s),4.13 (2H, t, J=8.4 Hz), 6.61 (1H, dd, J=8.4, 2.6 Hz), 6.70 (1H, d, J=2.6Hz), 7.03 (1H, d, J=8.4 Hz), 7.67 (1H, s), 7.71 (1H, s). elementaryanalysis as C₂₆H₃₀N₂O₃.HCl.H₂O calculation value: C, 66.02; H, 7.03; N,5.92. experimental value: C, 66.09; H, 7.30; N, 5.64.

Example 337(±)-8-[5-(2,3-Dihydro-1H-inden-1-ylamino)pentanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using tert-butyl(±)-2,3-dihydro-1H-inden-1-yl[5-oxo-5-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)pentyl]carbamate(332 mg) obtained in Reference Example 193 according to the same methodas that of Example 1, the title compound (57 mg) was obtained ascolorless crystals having a melting point of 98 to 100° C.

¹H NMR (200 MHz, DMSO-d₆) δ 1.50–1.75 (4H, m), 2.00–2.50 (2H, m), 2.54(2H, t, J=7.6 Hz), 2.75–3.05, (8H, m), 3.12 (2H, t, J=8.8 Hz), 3.94 (2H,t, J=8.8 Hz), 4.60–4.75 (1H, m), 7.20–7.35 (3H, m), 7.60–7.70 (3H, m).elementary analysis as C₂₅H₂₈N₂O₂.HCl.1.5H₂O calculation value: C,66.43; H. 7.14; N, 6.20. experimental value: C, 66.70; H, 6.77; N, 6.09.

Example 3388-[5-(2,3-Dihydro-1H-inden-2-ylamino)pentanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using tert-butyl2,3-dihydro-1H-inden-2-yl[5-oxo-5-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)pentyl]carbamate(461 mg) obtained in Reference Example 194 according to the same methodas that of Example 1, the title compound (275 mg) was obtained ascolorless crystals having a melting point of 187 to 189° C.

¹H NMR (200 MHz, DMSO-d₆) δ 1.60–1.80 (4H, m), 2.59 (2H, t, J=7.6 Hz),2.80–3.40 (12H, m), 3.80–4.05 (3H, m), 7.10–7.30 (4H, m), 7.75 (2H, s),9.40–9.60 (2H, br). elementary analysis as C₂₅H₂₈N₂O₂.HCl.2H₂Ocalculation value: C, 65.13; H, 7.22; N, 6.08. experimental value: C,64.75; H, 7.01; N, 6.02.

Example 3398-[5-(6,7-Dimethoxy-3,4-dihydro-2(1H)-isoquinolinyl)pentanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using8-(5-chloropentanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(1.00 g) obtained in Reference Example 1 and6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (945 mg) according to thesame method as that of Reference Example 19, the title compound (430 mg)was obtained as colorless crystals having a melting point of 215 to 217°C.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.60–2.00 (6H, m), 2.56 (2H, t,J=7.0 Hz), 2.65–3.10 (8H, m), 3.20 (2H, t, J=8.4 Hz), 3.55 (2H, s), 3.84(6H, s), 4.13 (2H, t, J=8.4 Hz), 6.52 (1H, s), 6.58 (1H, 3), 7.68 (1H,s), 7.72 (1H, s). elementary analysis as C₂₇H₃₂N₂O₄.HCl.H₂O calculationvalue: C, 64.47; H, 7.01; N, 5.57. experimental value: C, 64.74; H,7.25; N, 5.30.

Example 3408-[5-(1,2,4,5-Tetrahydro-3H-3-benzazepin-3-yl)pentanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using8-(5-chloropentanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(1.00 g) obtained in Reference Example 1 and2,3,4,5-tetrahydro-1H-3-benzazepine (605 mg) according to the samemethod as that of Reference Example 19, the title compound (703 mg) wasobtained as colorless crystals having a melting point of 252 to 254° C.

¹H NMR (free base; 200 MHz, CDCl₃) (1.50–1.85 (4H, m), 2.53 (2H, t,J=7.4 Hz), 2.60–3.10 (14H, m), 3.22 (2H, t, J=8.4 Hz), 4.13 (2H, t,J=8.4 Hz), 7.00–7.20 (4H, m), 7.68 (1H, s), 7.73 (1H, s).

Example 3418-{6-[2,3-Dihydro-1H-inden-2-yl(ethyl)amino]hexanoyl}-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using8-(6-bromohexanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(650 mg) obtained in Reference Example 2 andN-(2,3-dihydro-1H-inden-2-yl)-N-ethylamine (330 mg) according to thesame method as that of Reference Example 19, the title compound (366 mg)was obtained as colorless crystals having a melting point of 160 to 162°C.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.20 (3H, t, J=7.2 Hz), 1.30–1.85(6H, m), 2.50–3.30 (13H, m), 3.60–3.80 (4H, m), 4.10 (2H, t, J=8.4 Hz),7.05–7.25 (4H, m), 7.67 (1H, s), 7.71 (1H, s).

Example 3428-[6-(6,7-Dimethoxy-3,4-dihydro-2(1H)-isoquinolinyl)hexanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using8-(6-bromohexanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(600 mg) obtained in Reference Example 2 and6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (432 mg) according to thesame method as that of Reference Example 19, the title compound (540 mg)was obtained as colorless crystals having a melting point of 216 to 218°C.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.35–2.05 (8H, m), 2.51 (2H, t,J=7.6 Hz), 2.60–2.85 (4H, m), 2.93 (2H, t, J=7.6 Hz), 3.02 (2H, t, J=7.6Hz), 3.22 (2H, t, J=8.4 Hz), 3.55 (2H, s), 3.83 (6H, s), 4.13 (2H, t,J=8.4 Hz), 6.52 (1H, s), 6.59 (1H, s), 7.68 (1H, s), 7.72 (1H, s).elementary analysis as C₂₈H₃₄N₂O₄.HCl.2.5H₂O calculation value: C,61.81; H, 7.41; N, 5.15. experimental value: C, 62.26; H, 6.99; N, 5.14.

Example 3438-[6-(1,2,4,5-Tetrahydro-3H-3-benzazepin-3-yl)hexanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using8-(6-bromohexanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(600 mg) obtained in Reference Example 2 and2,3,4,5-tetrahydro-1H-3-benzazepine (277 mg) according to the samemethod as that of Reference Example 19, the title compound (566 mg) wasobtained as colorless crystals having a melting point of 222 to 225° C.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.30–1.85 (10H, m), 2.49 (2H, t,J=7.6 Hz), 2.60–2.80 (4H, m), 2.85–3.10 (6H, m), 3.21 (2H, t, J=8.4 Hz),4.13 (2H, t, J=8.4 Hz), 7.10 (4H, s), 7.67 (1H, s), 7.72 (1H, s).elementary analysis as C₂₇H₃₂N₂O₂.HCl.0.5H₂O calculation value: C,70.19; H, 7.42; N, 6.06. experimental value: C, 70.72; H, 7.13; N, 6.09.

Example 3449-(3-{1-[2-(2-Methylphenyl)ethyl]piperidin-4-yl}propanoyl)-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-onehydrochloride

Using9-(3-piperidin-4-ylpropanoyl)-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-one(326 mg) obtained in Reference Example 176 and 2-(2-methylphenyl)ethylmethanesulfonate (214 mg) according to the same method as that ofExample 81, the title compound (172 mg) was obtained as pale yellowamorphous powders.

¹H NMR (free base; 400 MHz, CDCl₃) δ 1.30–1.40 (3H, m), 1.68–1.78 (4H,m), 1.94–2.02 (4H, m), 2.32 (3H, s), 2.49–2.53 (2H, m), 2.68 (2H, t, J=7Hz), 2.80–2.86 (4H, m), 2.94 (4H, t, J=7 Hz), 3.04 (2H, t, J=11 Hz),3.89(2H, t, J=6 Hz), 7.09–7.15 (4H, m), 7.62 (2H, d, J=5 Hz). IR (neat)νcm⁻¹: 1674, 1604, 1489, 1361, 1339, 1168.

Example 3459-{5-[[2-(3-Fluorophenyl)ethyl](methyl)amino]pentanoyl}-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-onehydrochloride

Using9-(5-chloropentanoyl)-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-one(306 mg) obtained in Reference Example 5 andN-[2-(3-fluorophenyl)ethyl]-N-methylamine (337 mg) according to the samemethod as that of Example 9, the title compound (205 mg) was obtained aspale yellow amorphous powders.

¹H NMR (free base; 400 MHz, CDCl₃) δ 1.54–1.60 (2H, m), 1.70–1.77 (2H,m), 1.93–1.99 (2H, m), 2.29 (3H, s), 2.44 (2H, t, J=7.5 Hz), 2.58–2.62(2H, m), 2.67 (2H, t, J=6 Hz), 2.74–2.79 (2H, m), 2.84 (2H, t, J=6 Hz),2.91–2.96 (4H, m), 3.89 (2H, t, J=6 Hz), 6.85–6.91 (2H, m), 6.96 (1H, d,J=7.5 Hz), 7.19–7.25 (1H, m), 7.62 (2H, d, J=5 Hz). IR (neat) νcm⁻¹:1675, 1604, 1589, 1485, 1362, 1339, 1161.

Example 3466-{5-[(2-Phenylethyl)amino]pentanoyl}-3,4-dihydroquinolin-2(1H)-onehydrochloride

Using tert-butyl5-oxo-5-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pentyl(2-phenylethyl)carbamate(520 mg) obtained in Reference Example 345 according to the same methodas that of Example 1, the title compound was obtained as colorlesscrystals (390 mg) having a melting point of 200 to 202° C.

¹H NMR (400 MHz, DMSO-d₆) δ 1.64–1.76 (4H, m), 2.47–2.51 (2H, m),2.93–3.02 (8H, m), 3.05–3.15 (2H, m), 6.97 (1H, d, J=8.3 Hz), 7.22–7.27(3H, m), 7.31–7.35 (2H, m), 7.78–7.82 (2H, m), 9.25 (2H, s), 10.46 (1H,s). IR (KBr) νcm⁻¹: 3305, 2937, 2775, 1684, 1604, 1508, 1367.

Example 3476-(5-{[2-(2-Methoxyphenyl)ethyl]amino}pentanoyl)-3,4-dihydroquinolin-2(1H)-onehydrochloride

Using tert-butyl2-(2-methoxyphenyl)ethyl[5-oxo-5-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pentyl]carbamate(630 mg) obtained in Reference Example 197 according to the same methodas that of Example 1, the title compound was obtained as colorlesscrystals (449 mg) having a melting point of 176 to 177° C.

¹H NMR (400 MHz, DMSO-d₆) δ 1.63–1.72 (4H, m), 2.47–2.51 (2H, m),2.92–3.01(10H, m), 3.79 (3H, s), 6.90 (1H, t, J=7.5 Hz), 6.98 (2H, t,J=7.3 Hz), 7.18 (1H, d, J=7.3 Hz), 7.24 (1H, t, J=7.5 Hz), 7.78–7.82(2H, m), 9.16 (2H, s), 10.46 (1H, s). IR (KBr) νcm⁻¹: 3272, 2942, 2747,1682, 1602, 1501, 1369, 1312, 1253, 762.

Example 3486-(5-{[2-(2-Chlorophenyl)ethyl]amino}pentanoyl)-3,4-dihydroquinolin-2(1H)-onehydrochloride

Using tert-butyl2-(2-chlorophenyl)ethyl[5-oxo-5-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pentyl]carbamate(670 mg) obtained in Reference Example 198 according to the same methodas that of Example 1, the title compound was obtained as colorlesscrystals (450 mg having a melting point of 197 to 198° C.

¹H NMR (400 MHz, DMSO-d₆) δ 1.64–1.74 (4H, m), 2.47–2.51 (2H, m),2.92–3.10(10H, m), 6.96 (1H, d, J=8.3 Hz), 7.28–7.35 (2H, m), 7.39–7.47(2H, m), 7.78–7.82 (2H, m), 9.31 (2H, s), 10.45 (1H, s). IR (KBr) νcm⁻¹:3276, 2955, 2738, 1684, 1654, 1599, 1508, 1361, 1304, 1170,

Example 3496-(5-{[2-(2-Chlorophenyl)ethyl]amino}pentanoyl)-3,4-dihydroquinolin-2(1H)-onehydrochloride

Using 6-(5-chloropentanoyl)-3,4-dihydroquinolin-2(1H)-one (133 mg)obtained in Reference Example 195 andN-[2-(2-chlorophenyl)ethyl]-N-methylamine (187 mg) according to the samemethod as that of Example 9, the title compound was obtained ascolorless crystals (99 mg) having a melting point of 167 to 168° C.

¹H NMR (free base; 400 MHz, CDCl₃) δ 1.54–1.61 (2H, m), 1.71–1.79 (2H,m), 2.34 (3H, s), 2.47 (2H, t, J=7.3 Hz), 2.59–2.63 (2H, m), 2.68 (2H,t, J=8 Hz), 2.88–2.97 (4H, m), 3.04 (2H, t, J=7.3 Hz), 6.85 (1H, d,J=6.4 Hz), 7.10–7.19 (2H, m), 7.23 (1H, d, J=7.5 Hz), 7.32 (1H, d, J=7.5Hz), 7.80 (1H, d, J=6.4 Hz), 7.81 (1H, s), 8.95 (1H, br). IR (KBr)νcm⁻¹: 3188, 3059, 1674, 1608, 1595, 1384, 1314, 816, 751.

Example 3506-{6-[(2-Phenylethyl)amino]hexanoyl}-3,4-dihydroquinolin-2(1H)-onehydrochloride

Using 6-(6-bromohexanoyl)-3,4-dihydroquinolin-2(1H)-one (486 mg)obtained in Reference Example 199 and 2-phenylethylamine (454 mg)according to the same method as that of Example 9, the title compoundwas obtained as colorless crystals (205 mg) having a melting point of223 to 224° C.

¹H NMR (free base; 400 MHz, CDCl₃) δ 1.35–1.42 (2H, m), 1.46 (1H, br.s),1.49–1.56(2H, m), 1.69–1.77(2H, m), 2.62–2.70 (4H, m), 2.80 (2H, t, J=6Hz), 2.86–2.92 (4H, m), 3.03 (2H, t, J=7.4 Hz), 6.83 (1H, d, J=7 Hz),7.16–7.18 (3H, m), 7.27–7.31 (2H, m), 7.79 (1H, d, J=7 Hz), 7.80 (1H,s), 8.93 (1H, br). IR (KBr) νcm⁻¹: 3193, 3062, 1671, 1605, 1505, 1381,1314.

Example 3516-(6-{[2-(2-Methoxyphenyl)ethyl]amino}hexanoyl)-3,4-dihydroquinolin-2(1H)-onehydrochloride

Using 6-(6-bromohexanoyl)-3,4-dihydroquinolin-2(1H)-one (486 mg)obtained in Reference Example 199 and 2-(2-methoxyphenyl)ethylamine (567mg) according to the same method as that of Example 9, the titlecompound was obtained as colorless crystals (122 mg) having a meltingpoint of 223 to 224° C.

¹H NMR (free base; 400 MHz, CDCl₃) δ 1.35–1.43 (2H, m), 1.49–1.57 (2H,m), 1.53 (1H, br), 1.69–1.77(2H, m), 2.62–2.69 (4H, m), 2.78–2.86 (4H,m), 2.90 (2H, t, J=7 Hz), 3.03 (2H, t, J=7 Hz), 3.81 (3H, s), 6.81–6.89(3H, m), 7.13–7.20 (2H, m), 7.78 (1H, d, J=7 Hz), 7.79 (1H, s), 9.30(1H, br). IR (KBr) νcm⁻¹: 3192, 3061, 1677, 1608, 1495, 1367, 1317,1243.

Example 3526-(6-{[2-(2-Chlorophenyl)ethyl]amino}hexanoyl)-3,4-dihydroquinolin-2(1H)-onehydrochloride

Using 6-(6-bromohexanoyl)-3,4-dihydroquinolin-2(1H)-one (486 mg)obtained in Reference Example 199 and 2-(2-chlorophenyl)ethylamine (584mg) according to the same method as that of Example 9, the titlecompound was obtained as colorless crystals (196 mg) having a meltingpoint of 213 to 214° C.

¹H NMR (free base; 400 MHz, CDCl₃) δ 1.37–1.45 (2H, m), 1.49 (1H, br),1.51–1.58(2H, m), 1.71–1.78 (2H, m), 2.65–2.70 (4H, m), 2.86–2.96 (6H,m), 3.04 (2H, t, J=7 Hz), 6.85 (1H, d, J=7 Hz), 7.12–7.31 (3H, m), 7.34(1H, d, J=7.4 Hz), 7.80 (1H, d, J=7 Hz), 7.81 (1H, s), 8.93 (1H, br). IR(KBr) νcm⁻¹: 3191, 3059, 1672, 1608, 1506, 1380, 1316.

Example 3536-(5-{[2-(2-Methoxyphenyl)ethyl]amino}pentanoyl)-1-methyl-3,4-dihydroquinolin-2(1H)-onehydrochloride

Using tert-butyl2-(2-methoxyphenyl)ethyl[5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-5-oxopentyl]carbamate(220 mg obtained in Reference Example 200 according to the same methodas that of Example 1, the title compound was obtained as colorlesscrystals (184 mg) having a melting point of 167 to 168° C.

¹H NMR (400 MHz, DMSO-d₆) δ 1.52–1.68 (4H, m), 2.49 (2H, t, J=8 Hz),2.83–2.96(10H, m), 3.19 (3H, s), 3.71 (3H, s), 6.81 (1H, t, J=7.5 Hz),6.90 (1H, t, J=8.3 Hz), 7.08–7.11 (2H, m), 7.16 (1H, d, J=7.5 Hz), 7.76(1H, s), 7.80 (1H, d, J=8.3 Hz), 9.10 (2H, s). IR (KBr νcm⁻¹: 2951,2783, 2453, 1688, 1606, 1494, 1469, 1354, 1248, 1125, 766.

Example 3546-(5-{[2-(2-Chlorophenyl)ethyl]amino}pentanoyl)-3,4-dihydroquinolin-2(1H)-onehydrochloride

Using tert-butyl2-(2-chlorophenyl)ethyl[5-(1-methyl-2-oxo-1,2,3,4-tetrahydro-6-quinolinyl)-5-oxopentyl]carbamate(240 mg) obtained in Reference Example 201 according to the same methodas that of Example 1, the title compound was obtained as colorlesscrystals (193 mg) having a melting point of 102 to 103° C.

¹H NMR (400 MHz, DMSO-d₆) δ 1.52–1.68 (4H, m), 2.49 (2H, t, J=8 Hz),2.87–3.07(10H, m), 3.19 (3H, s), 7.10 (1H, d, J=8.5 Hz), 7.19–7.26 (2H,m), 7.32 (1H, dd, J=7, 2 Hz), 7.37 (1H, dd, J=7, 2 Hz), 7.76 (1H, s),7.81 (1H, d, J=8.5 Hz), 9.25 (2H, s). IR (KBr) νcm⁻¹: 2947, 2768, 2453,1671, 1604, 1477, 1443, 1355, 1126, 751.

Example 3556-{5-[[2-(2-Methoxyphenyl)ethyl](methyl)amino]pentanoyl}-1-methyl-3,4-dihydroquinolin-2(1H)-onehydrochloride

Using 6-(5-chloropentanoyl)-1-methyl-3,4-dihydroquinolin-2(1H)-one (224mg) obtained in Reference Example 154 andN-[2-(2-methoxyphenyl)ethyl]-N-methylamine (291 mg) according to thesame method as that of Example 9, the title compound was obtained aspale yellow amorphous powders (165 mg).

¹H NMR (free base; 400 MHz, CDCl₃) δ 1.55–1.62 (2H, m), 1.72–1.80(2H,m), 2.32 (3H, s) 2.46 (2H, t, J=7.3 Hz), 2.55–2.59 (2H, m), 2.68 (2H, t,J=7.5 Hz), 2.76–2.81 (2H, m), 2.93–2.98 (4H, m), 3.38 (3H, s), 3.81 (3H,s), 6.82–6.90 (2H, m), 7.01 (1H, d, J=8.5 Hz), 7.12–7.19, (2H, m), 7.79(1H, d, J=2 Hz), 7.87 (1H, dd, J=8.5, 2 Hz). IR (KBr) νcm⁻¹: 2941, 1679,1604, 1495, 1466, 1354, 1243, 1126.

Example 3566-{5-[[2-(2-Chlorophenyl)ethyl](methyl)amino]pentanoyl}-1-methyl-3,4-dihydroquinolin-2(1H)-onehydrochloride

Using 6-(5-chloropentanoyl)-1-methyl-3,4-dihydroquinolin-2(1H)-one (224mg) obtained in Reference Example 154 andN-[2-(2-chlorophenyl)ethyl]-N-methylamine (299 mg) according to the samemethod as that of Example 9, the title compound was obtained ascolorless crystals (200 mg) having a melting point of 129 to 130° C.

¹H NMR (free base; 400 MHz, CDCl₃) δ 1.54–1.62 (2H, m), 1.72–1.79 (2H,m), 2.33 (3H, s) 2.47 (2H, t, J=7.3 Hz), 2.59–2.63 (2H, m), 2.68 (2H, t,J=7.3 Hz), 2.88–2.99 (6H, m), 3.39 (3H, s), 7.02 (1H, d, J=8.5 Hz),7.10–7.19 (2H, m), 7.23 (1H, dd, J=7.3, 2 Hz), 7.32 (1H, dd, J=8, 2 Hz),7.79 (1H, d, J=2 Hz), 7.87 (1H, dd, J=8.5, 2 Hz). IR (KBr) νcm⁻¹: 2943,1679, 1605, 1474, 1354, 1305, 1126.

Example 357(±)-8-{5-[[2-(2-Chlorophenyl)ethyl](methyl)amino]hexanoyl}-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

7.8 g of Polyphosphoric acid was placed in a 100 ml four-neck flask, theflask was warmed to 50 to 60° C., and 520 mg (3 mmol) of1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one and 850 mg (3.3mmol) of (±)-5-[[2-(2-chlorophenyl)ethyl](methyl)amino]hexanoic acidobtained in Reference Example 202 were added. After stirring at anexternal temperature of 110° C. for 15 hours, ice-water (20 ml) wasadded to dissolve the reaction mixture, and 8N—NaOH (about 20 ml) wasadded to adjust to pH 7 to 8. The liberated oil was extracted with ethylacetate (30 ml), washed successively with each (20 ml) of water andbrine, dried over MgSO₄ and concentrated. The residue was purified bycolumn (basic silica gel: 80 g, developing solvent:ethylacetate-hexane=1:1) to give a free base compound of the title compoundas a pale yellow oil (660 mg).

¹H NMR (free base; 400 MHz, CDCl₃) δ 0.95(3H, d, J=6.6 Hz), 1.30–1.37(1H, m), 1.50–1.59 (1H, m), 1.68–1.76, (2H, m), 2.30 (3H, s), 2.50–2.58;(1H, m), 2.61–2.73 (4H, m), 2.84–2.89 (4H, m), 3.02 (2H, t, J=7.6 Hz),3.22 (2H, t, J=8.3 Hz), 4.13 (2H, t, J=7.0 Hz), 7.08–7.18 (2H, m),7.23(1H, dd, J=7.8, 1.5 Hz), 7.30 (1H, dd, J=7.8, 1.5 Hz), 7.67, (1H,s), 7.72 (1H, s). IR (neat) νcm⁻¹: 1674, 1598, 1494, 1447, 1381, 1330,1155, 753.

The thus obtained base compound (650 mg) was dissolved in ethyl acetate(1 ml), and 4N-hydrochloric acid (ethyl acetate solution) (0.5 ml) wasadded at room temperature. After stirring at room temperature for 30minutes, the reaction mixture was concentrated, ethyl acetate (2 ml) wasadded to the residue, and the precipitated crystals were collected byfiltration to give the title compound (568 mg) as fine yellow powdershaving a melting point of 93 to 95° C.

Example 358(±)-8-{5-[[2-(2-Chlorophenyl)ethyl](methyl)amino]hexanoyl}-5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-onehydrochloride

Using 520 mg (3 mmol) of5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-one and 850 mg (3.3 mmol)of (±)-5-[[2-(2-chlorophenyl)ethyl](methyl)amino]hexanoic acid obtainedin Reference Example 202 according to the same method as that of Example357, a free base compound of the title compound was obtained as a paleyellow oil (456 mg).

¹H NMR (free base; 400 MHz, CDCl₃) δ 0.96 (3H, d, J=6.4 Hz), 1.30–1.37(1H, m), 1.52–1.60(1H, m), 1.68–1.77 (2H, m), 2.00–2.06 (2H, m),2.31(3H, s), 2.52–2.59 (1H, m), 2.62–2.75 (2H, m), 2.81–2.90 (6H, m),3.54 (2H, s), 3.74 (2H, t, J=6.0 Hz), 7.10 (1H, dt, J=7.3, 1.7 Hz), 7.16(1H, dt, J=7.3, 1.7 Hz), 7.23 (1H, dd, J=7.6, 1.7 Hz), 7.30 (1H, dd,J=7.6, 1.7 Hz), 7.73 (2H, s). IR (neat) νcm⁻¹: 1718, 1673, 1604, 1496,1343, 1154, 753.

The thus obtained free base compound (440 mg) was dissolved in ethylacetate (1 ml), and 4N-hydrochloric acid (ethyl acetate solution) (0.5ml) was added at room temperature. After stirring at room temperaturefor 30 minutes, the reaction mixture was concentrated, ethyl acetate (2ml) was added to the residue, and the precipitated crystals werecollected by filtration to give the title compound(420 mg) as fineyellow powders having a melting point of 63 to 65° C.

Example 359(±)-1,3-Dimethyl-5-[5-[[2-(2-chlorophenyl)ethyl](methyl)amino]hexanoyl]-1,3-dihydro-2H-benzimidazol-2-onehydrochloride

Using 484 mg (3 mmol) of 1,3-dimethyl-1,3-dihydro-2H-benzimidazol-2-oneand 850 mg (3.3 mmol) of(±)-5-[[2-(2-chlorophenyl)ethyl](methyl)amino]hexanoic acid obtained inReference Example 202 according to the same method as that of Example, afree base compound of the title compound (860 mg) was obtained as a paleyellow oil.

¹H NMR (free base; 400 MHz, CDCl₃) δ 0.96 (3H, d, J=6.46 Hz), 1.32–1.39(1H, m), 1.54–1.59 (1H, m), 1.71–1.77 (2H, m), 2.31(3H, s), 2.51–2.58(1H, m), 2.61–2.75 (2H, m), 2.82–2.99 (4H, m), 3.45 (3H, s), 3.46 (3H,s), 6.99 (1H, d, J=8.3 Hz), 7.09 (1H, dt, J=7.3, 1.7 Hz), 7.15 (1H, dt,J=7.3, 1.7 Hz), 7.23 (1H, dd, J=7.6, 1.7 Hz), 7.30 (1H, dd, J=7.6, 1.7Hz), 7.62 (1H, d, J=1.5 Hz), 7.78 (1H, dd, J=8.3, 1.5 Hz). IR (KBr)νcm⁻¹: 1720, 1676, 1622, 1511, 1475, 1395, 1195, 750, 584

The thus obtained free base compound (850 mg) was dissolved in ethylacetate (2 ml), and 4N-hydrochloric acid (ethyl acetate solution) (0.5ml) was added at room temperature. After stirring at room temperaturefor 30 minutes, the reaction mixture was concentrated, ethyl, acetate (2ml) was added to the residue, and the precipitated crystals werecollected by filtration to give the title compound (900 mg) as fineyellow amorphous powders.

Example 3608-(5-{[2-(2-Chlorophenyl)ethyl]amino}pentanoyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-onep-toluenesulfonate

8-(5-{[2-(2-Chlorophenyl)ethyl]amino}pentanoyl)-5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinolin-2(1H)-onehydrochloride (205 mg, 0.5 mmol) obtained in Example 39 was mixed with a1 N aqueous sodium hydroxide solution (10 ml), and extracted with ethylacetate (30 ml×3. The organic layer was washed with aqueous saturatedsodium chloride, dried over anhydrous sodium sulfate, and the solventwas evaporated. To the resulting residue was added ethanol (3 ml) togive a solution. Then, a solution of p-toluenesulfonic acid monohydrate(95 mg, 0.5 mmol) in ethanol (3 mmol) was added thereto, the mixture wasstirred, and the ethanol (about 5.5 ml) was evaporated under reducedpressure. The residue was allowed to stand at room temperature, and theprecipitated crystals were collected by filtration, and washedsuccessively with ethanol and diethyl ether. Further drying underreduced pressure afforded the title compound as colorless crystals (258mg) having a melting point of 172 to 173° C. (dec). elementary analysisas C₂₄H₂₇ClN₂O₂.C₇H₈O₃S calculation value: C, 63.85; H, 6.05; N, 4.80.experimental value: C, 63.77; H, 5.99; N, 4.69.

Example 3618-(5-{[2-(2-Chlorophenyl)ethyl]amino}pentanoyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-onesulfate

Using8-(5-{[2-(2-chlorophenyl)ethyl]amino}pentanoyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-onehydrochloride (205 mg, 0.5 mmol) obtained in Example 39 and sulfuricacid (49 mg, 0.5 mmol) according to the same method as that of Example360, the title compound was obtained as colorless crystals (218 mg)having a melting point of 155 to 156° C. (dec). elementary analysis asC₂₄H₂₇ClN₂O₂.H₂SO₄ calculation value: C, 56.63; H, 5.74; N, 5.50.experimental value: C, 56.42; H, 5.86; N, 5.23.

Example 3628-(5-{[2-(2-Chlorophenyl)ethyl]amino}pentanoyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-onehydrobromide

Using8-(5-{[2-(2-chlorophenyl)ethyl]amino}pentanoyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-onehydrochloride (205 mg, 0.5 mmol) obtained in Example 39 and 48%hydrobromic acid (84 mg, 0.5 mmol) according to the same method as thatof Example 360, the title compound was obtained as colorless crystals(220 mg) having a melting point of 201 to 203° C. (dec). elementaryanalysis as C₂₄H₂₇ClN₂O₂.HBr calculation value: C, 58.61; H, 5.74; N,5.70. experimental value: C, 58.54; H, 5.85; N, 5.53.

Example 3635-{[2-(2-Chlorophenyl)ethyl]amino}-1-(2,3-dihydro-2,2-dimethyl-1-benzofuran-5-yl)pentan-1-onehydrochloride

Using tert-butyl5-(2,3-dihydro-2,2-dimethyl-1-benzofuran-5-yl)-5-oxopentyl[2-(2-chlorophenyl)ethyl]carbamate(550 mg) obtained in Reference Example 209 according to the same methodas that of Example 1, the title compound was obtained as colorlesscrystals (350 mg) having a melting point of 132 to 133° C.

¹H NMR (400 MHz, DMSO-d₆) δ 1.42 (6H, s), 1.61–1.75 (4H, m), 2.93–3.16(10H, m), 6.78 (1H, t, J=8.3 Hz), 7.30–7.46 (4H, m), 7.79 (1H, d, J=8.3Hz), 7.83 (1H, s), 9.36 (2H, br). IR (KBr) νcm⁻¹: 2946, 1668, 1603,1440, 1266, 1090, 750.

Example 3645-{[2-(2-Chlorophenyl)ethyl]amino}-1-(3,4-dihydro-2H-chromen-6-yl)-1-pentanonehydrochloride

Using tert-butyl5-(3,4-dihydro-2H-chromen-6-yl)-5-oxopentyl[2-(2-chlorophenyl)ethyl]carbamate(750 mg) obtained in Reference Example 210 according to the same methodas that of Example 1, the title compound was obtained as colorlesscrystals (586 mg) having a melting point of 154 to 155° C.

¹H NMR (400 MHz, DMSO-d₆) δ 1.62–1.72 (4H, m), 1.91 (2H, br.s), 2.77(2H, br.s) 2.95–2.98 (4H, m), 3.08–3.15 (4H, m), 4.18 (2H, br.s), 6.79(1H, d, J=8.3 Hz), 7.26–7.44 (4H, m), 7.69 (1H, d, J=8.3 Hz), 7.72 (1H,s), 9.19 (2H, br.s). IR (KBr) νcm⁻¹: 2958, 1673, 1605, 1499, 1476, 1257,1138, 1019, 758.

Example 365N-methyl-5-(5-{[2-(2-methoxyphenyl)ethyl]amino}pentanoyl)-2,3-dihydro-1-benzofuran-7-sulfonamidehydrochloride

Using tert-butyl5-{7-[(methylamino)sulfonyl]-2,3-dihydro-1-benzofuran-5-yl}-5-oxopentyl[2-(2-methoxyphenyl)ethyl]carbamate(850 mg) obtained in Reference Example 211 according to the same methodas that of Example 1, the title compound was obtained as colorlesscrystals (673 mg) having a melting point of 167 to 168° C.

¹H NMR (400 MHz, DMSO-d₆) δ 1.62–1.76 (4H, m), 2.45 (3H, d, J=4.8 Hz),2.94–3.05 (8H, m), 3.31 (2H, t, J=8.8 Hz), 3.79 (3H, s), 4.80 (2H, t,J=8.8 Hz), 6.89 (1H, t, J=7.6 Hz), 6.98 (1H, d, J=8.0 Hz), 7.17(1H, d,J=7.6 Hz), 7.24 (1H, t, J=8.0 Hz), 7.47(1H, br.s), 8.05 (1H, s), 8.09(1H, s), 9.19 (2H, br). IR (KBr) νcm⁻¹: 3319, 2783, 2453, 1686, 1605,1496, 1467, 1334, 1255, 1157, 1119, 758, 586.

Example 366N-Methyl-5-(5-{[2-(2-chlorophenyl)ethyl]amino}pentanoyl)-2,3-dihydro-1-benzofuran-7-sufonamidehydrochloride

Using tert-butyl5-{7-[(methylamino)sulfonyl]-2,3-dihydro-1-benzofuran-5-yl}-5-oxopentyl[2-(2-chlorophenyl)ethyl]carbamate(500 mg) obtained in Reference Example 212 according to the same methodas that of Example 1, the title compound was obtained as colorlesscrystals (430 mg) having a melting point of 182 to 183° C.

¹H NMR (400 MHz, DMSO-d₆) δ 1.62–1.76 (4H, m), 2.45 (3H, d, J=4.8 Hz),2.97–3.11 (8H, m), 3.31 (2H, t, J=8.8 Hz), 4.80 (2H, t, J=8.8 Hz),7.28–7.34 (2H, m), 7.39–7.41 (1H, m), 7.44–7.47 (2H, m), 8.05 (1H, s),8.09 (1H, s), 9.28 (2H, br). IR (KBr) νcm⁻¹: 3155, 2808, 1677, 1613,1480, 1431, 1326, 1228, 1150, 766, 588.

Example 367N,N-Dimethyl-5-(5-{[2-(2-methoxyphenyl)ethyl]amino}pentanoyl)-2,3-dihydro-1-benzofuran-7-sulfonamidehydrochloride

Using tert-butyl5-{7-[(dimethylamino)sulfonyl]-2,3-dihydro-1-benzofuran-5-yl}-5-oxopentyl[2-(2-methoxyphenyl)ethyl]carbamate(860 mg) obtained in Reference Example 213 according to the same methodas that of Example 1, the title compound was obtained as colorlesscrystals (636 mg) having a melting point of 164 to 165° C.

¹H NMR (400 MHz, DMSO-d₆) δ 1.62–1.75 (4H, m), 2.70 (6H, s), 2.93–3.06(8H, m), 3.31 (2H, t, J=8.8 Hz), 3.79 (3H, s), 4.79 (2H, t, J=8.8 Hz),6.89 (1H, t, J=7.6 Hz), 6.98 (1H, d, J=8.0 Hz), 7.17 (1H, d, J=7.6 Hz),7.23 (1H, t, J=8.0 Hz), 8.00 (1H, s), 8.13(1H, s), 9.17 (2H, br). IR(KBr) νcm⁻¹: 2783, 1684, 1604, 1496, 1463, 1424, 1338, 1250, 1152, 1126,956, 766, 585.

Example 368N-Dimethyl-5-(5-{[2-(2-chlorophenyl)ethyl]amino}pentanoyl)-2,3-dihydro-1-benzofuran-7-sulfonamidehydrochloride

Using tert-butyl2-(2-chlorophenyl)ethyl(5-{7-[(dimethylamino)sulfonyl]-2,3-dihydro-1-benzofuran-5-yl}-5-oxopentyl)carbamate(500 mg) obtained in Reference Example 214 according to the same methodas that of Example 1, the title compound was obtained as colorlesscrystals (417 mg) having a melting point of 176 to 177° C.

¹H NMR (400 MHz, DMSO-d₆) δ 1.62–1.75 (4H, m), 2.70 (6H, s), 2.97–3.14(8H, m), 3.32 (2H, t, J=8.8 Hz), 4.79 (2H, t, J=8.8 Hz), 7.29–7.33 (2H,m), 7.40 (1H, dd, J=7.0, 1.7 Hz), 7.45 (1H, dd, J=7.0, 1.7 Hz), 8.00(1H, s), 8.13 (1H, s), 9.21 (2H, br). IR (KBr) νcm⁻¹: 2776, 1684, 1601,1461, 1424, 1334, 1265, 1151, 1121, 963, 758, 758, 584.

Example 3696-(5-{[2-(2-Methoxyphenyl)ethyl]amino}pentanoyl)-8-chromansulfonamidehydrochloride

Using tert-butyl5-[8-(aminosulfonyl)-3,4-dihydro-2H-chromen-6-yl]-5-oxopentyl[2-(2-methoxyphenyl)ethyl]carbamate(650 mg) obtained in Reference Example, 215 according to the same methodas that of Example 1, the title compound was obtained as colorlesscrystals (560 mg) having a melting point of 184 to 185° C.

¹H NMR (400 MHz, DMSO-d₆) δ 1.61–1.73 (4H, m), 1.95–1.98(2H, m), 2.86(2H, t, J=6.2 Hz), 2.93–3.03 (8H, m), 3.78 (3H, s), 4.36 (2H, t, J=5.1Hz), 6.89 (1H, t, J=7.3 Hz), 6.97 (1H, d, J=8.0 Hz), 7.16–7.25 (2H, m),7.19 (2H, s), 7.96 (1H, d, J=2.0 Hz), 8.12 (1H, d, J=2.0 Hz), 9.23 (2H,br.s). IR (KBr) νcm⁻¹: 3306; 3209, 2947, 1661, 1602, 1573, 1495, 1342,1244, 1161, 1140, 766, 591.

Example 3706-(5-{[2-(2-Chlorophenyl)ethyl]amino}pentanoyl)-8-chromansulfonamidehydrochloride

Using tert-butyl5-[8-(aminosulfonyl)-3,4-dihydro-2H-chromen-6-yl]-5-oxopentyl[2-(2-chlorophenyl)ethyl]carbamate(650 mg) obtained in Reference Example 216 according to the same methodas that of Example 1, the title compound was obtained as colorlesscrystals (564 mg) having a melting point of 177 to 178° C.

¹H NMR (400 MHz, DMSO-d₆) δ 1.63–1.73 (4H, m), 1.95–1.99 (2H, m), 2.86(2H, t, J=6.2 Hz), 2.96 (2H, br.s), 3.02 (2H, t, J=7.0 Hz), 3.09–3.16(4H, m), 4.36 (2H, t, J=5.1 Hz), 7.19(2H, s), 7.28–7.33 (2H, m), 7.40(1H, dd, J=7, 2.2 Hz), 7.44 (1H, dd, J=7, 2.2 Hz), 7.96 (1H, d, J=2.0Hz), 8.11 (1H, d, J=2.0 Hz), 9.36 (2H, s). IR (KBr) νcm⁻¹: 3307, 3208,1662, 1602, 1573, 1474, 1342, 1161, 1140, 1004, 907, 765, 591.

Example 3715-{5-[[2-(2-Methoxyphenyl)ethyl](methyl)amino]pentanoyl}-N-methyl-2,3-dihydro-1-benzofuran-7-sulfonamidehydrochloride

Using5-(5-chloropentanoyl)-N-methyl-2,3-dihydro-1-benzofuran-7-sulfonamide(664 mg) obtained in Reference Example 203 andN-[2-(2-methoxyphenyl)ethyl]-N-methylamine (752 mg) according to thesame method as that of Example 9, the title compound (246 mg) wasobtained as pale yellow amorphous powders.

¹H NMR (free base; 400 MHz, CDCl₃) δ 1.54–1.61 (2H, m), 1.71–1.78 (2H,m), 2.32 (3H, s), 2.46 (2H, t, J=7.3 Hz), 2.56–2.60 (2H, m), 2.65 (3H,s), 2.76–2.80 (2H, m), 2.96 (2H, t, J=7.0 Hz), 3.33 (2H, t, J=8.8 Hz),3.82 (3H, s), 4.82–4.85 (1H, br), 4.86 (2H, t, J=8.8 Hz), 6.83–6.89 (2H,m), 7.12–7.19 (2H, m), 8.04 (1H, d, J=1.6 Hz), 8.22 (1H, d, J=1.6 Hz).IR (neat) νcm⁻¹: 3307, 1679, 1602, 1495, 1465, 1330, 1244, 1160, 1118,756, 734, 587.

Example 3725-{5-[[2-(2-Chlorophenyl)ethyl](methyl)amino]pentanoyl}-N-methyl-2,3-dihydro-1-benzofuran-7-sulfonamidehydrochloride

Using5-(5-chloropentanoyl)-N-methyl-2,3-dihydro-1-benzofuran-7-sulfonamide(664 mg) obtained in Reference Example 203 andN-[2-(2-chlorophenyl)ethyl]-N-methylamine (768 mg) according to the samemethod as that of Example 9, the title compound (360 mg) was obtained aspale yellow amorphous powders.

¹H NMR (free base; 400 MHz, CDCl₃) δ 1.54–1.61 (2H, m), 1.71–1.78 (2H,m), 2.34 (3H, s), 2.48 (2H, t, J=7.6 Hz), 2.60–2.64, (2H, m), 2.66 (3H,d, J=4.4 Hz), 2.89–2.98 (4H, m), 3.34 (2H, t, J=8.8 Hz), 4.77 (1H,br.s), 4.87 (2H, t, J=8.8 Hz), 7.13 (1H, dt, J=7.6, 1.5 Hz), 7.18 (1H,dt, J=7.6, 1.5 Hz), 7.24 (1H, dd, J=7.6, 1.5 Hz), 7.32 (1H, dd, J=7.6,1.5 Hz), 8.06 (1H, d, J=1.5 Hz), 8.23 (1H, d, J=1.5 Hz). IR (neat)νcm⁻¹: 3307, 1680, 1603, 1475, 1329, 1263, 1159, 1119, 754, 585.

Example 3735-{5-[[2-(2-Methoxyphenyl)ethyl](methyl)amino]pentanoyl}-N,N-dimethyl-2,3-dihydro-1-benzofuran-7-sulfonamidehydrochloride

Using5-(5-chloropentanoyl)-N,N-dimethyl-2,3-dihydro-1-benzofuran-7-sulfonamide(692 mg) obtained in Reference Example 204 andN-[2-(2-methoxyphenyl)ethyl]-N-methylamine (752 mg) according to thesame method as that of Example 9, the title compound (466 mg) wasobtained as pale yellow amorphous powders.

¹H NMR (free base; 400 MHz, CDCl₃) δ 1.56–1.63 (2H, m), 1.71–1.79 (2H,m), 2.34 (3H, s), 2.49 (2H, t, J=7.6 Hz), 2.58–2.62 (2H, m), 2.78–2.82(2H, m), 2.84 (6H, s), 2.95 (2H, t, J=7.3 Hz), 3.32 (2H, t, J=7.3 Hz),3.82 (3H, s), 4.82 (2H, t, J=8.8 Hz), 6.83–6.89 (2H, m), 7.13–7.19 (2H,m), 8.02 (1H, d, J=1.7 Hz), 8.19 (1H, d, J=1.7 Hz). IR (neat) νcm⁻¹:3307, 1680, 1603, 1475, 1329, 1263, 1159, 1119, 754, 585.

Example 3745-{5-[[2-(2-Chlorophenyl)ethyl](methyl)amino]pentanoyl}-N,N-dimethyl-2,3-dihydro-1-benzofuran-7-sulfonamidehydrochloride

Using5-(5-chloropentanoyl)-N,N-dimethyl-2,3-dihydro-1-benzofuran-7-sulfonamide(692 mg) obtained in Reference Example 204 andN-[2-(2-chlorophenyl)ethyl]-N-methylamine (768 mg) according to the samemethod as that of Example 9, the title compound (370 mg) was obtained aspale yellow amorphous powders.

¹H NMR (free base; 400 MHz, CDCl₃) δ 1.53–1.61 (2H, m), 1.70–1.78 (2H,m), 2.33 (3H, s), 2.47 (2H, t, J=7.6 Hz), 2.59–2.63 (2H, m), 2.84 (6H,s), 2.87–2.96 (4H, m), 3.32 (2H, t, J=8.8 Hz), 4.82 (2H, t, J=8.8 Hz),7.12 (1H, dt, J=7.6, 1.5 Hz), 7.17 (1H, dt, J=7.6, 1.5 Hz), 7.24 (1H,dd, J=7.6, 1.5 Hz), 7.32, (1H, dd, J=7.6, 1.5 Hz), 8.02. (1H, d, J=1.5Hz), 8.18 (1H, d, J=1.5 Hz). IR (neat) νcm⁻¹: 1681, 1603, 1464, 1423,1342, 1262, 1154, 1119, 958, 754, 583.

Example 3756-{5-[[2-(2-Methoxyphenyl)ethyl](methyl)amino]pentanoyl}-8-chromansulfonamidehydrochloride

Using 6-(5-chloropentanoyl)-8-chromansulfonamide (664 mg) obtained inReference Example 208 and N-[2-(2-methoxyphenyl)ethyl]-N-methylamine(752 mg) according to the same method as that of Example 9, the titlecompound was obtained as colorless crystals (447 mg) having a meltingpoint of 121 to 122° C.

¹H NMR (free base; 400 MHz, CDCl₃) δ 1.51–1.59 (2H, m), 1.68–1.75 (2H,m), 2.09–2.15 (2H, m), 2.30 (3H, s), 2.42–2.46 (2H, m), 2.54–2.58 (2H,m), 2.74–2.78 (2H, m), 2.88–2.93 (4H, m), 3.82 (3H, s), 4.47 (2H, t,J=5.3 Hz), 5.17 (2H, br.s), 6.82–6.88 (2H, m), 7.11–7.19 (2H, m), 7.91(1H, d, J=1.7 Hz), 8.28 (1H, d, J=1.7 Hz). IR (neat) νcm⁻¹: 3388, 3283,1684, 1600, 1461, 1324, 1243, 1165, 1144, 1032, 752,

Example 3766-{5-[[2-(2-Chlorophenyl)ethyl](methyl)amino]pentanoyl}-8-chromansulfonamidehydrochloride

Using 6-(5-chloropentanoyl)-8-chromansulfonamide (664 mg) obtained inReference Example 208 and N-[2-(2-chlorophenyl)ethyl]-N-methylamine (768mg) according to the same method as that of Example 9, the titlecompound (360 mg) was obtained as pale yellow amorphous powders.

¹H NMR (free base; 400 MHz, CDCl₃) δ 1.51–1.59 (2H, m), 1.68–1.75 (2H,m), 2.09–2.15 (2H, m), 2.32 (3H, s), 2.46 (2H, t, J=7.3 Hz), 2.58–2.62(2H, m), 2.87–2.93 (6H, m), 4.48 (2H, t, J=5.3 Hz), 5.31 (2H, br.s),7.12 (1H, dt, J=7.3, 2 Hz), 7.17 (1H, dt, J=7.3, 2 Hz), 7.22 (1H, dd,J=7.3, 1.7 Hz), 7.32 (1H, dd, J=7.3, 1.7 Hz), 7.90 (1H, d, J=1.7 Hz),8.27 (1H, d, J=1.7 Hz). IR (neat) νcm⁻¹: 3384, 3276, 1684, 1599, 1477,1324, 1161, 1144, 901, 757.

Example 3778-(5-{[2-(2-Chlorophenyl)ethyl]amino}pentanoyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-onecitrate

Using8-(5-{[2-(2-chlorophenyl)ethyl]amino}pentanoyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-onehydrochloride (205 mg, 0.5 mmol) obtained in Example 39 and citric acid(96 mg, 0.5 mmol) according to the same method as that of Example 360,the title compound was obtained as colorless crystals (278 mg) having amelting point of 100 to 102° C. (dec). elementary analysis asC₂₄H₂₇ClN₂O₂.C₆H₈O₇ calculation value: C, 59.75; H, 5.85; N, 4.65.experimental value: C, 59.34; H, 6.21; N, 4.39.

Example 3788-(5-{[2-(2-Chlophenyl)ethyl]amide}pentanoyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-onesuccinate

Using8-(5-{[2-(2-chlorophenyl)ethyl]amino}pentanoyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-onehydrochloride (205 mg, 0,5 mmol) obtained in Example 39 and succinicacid (59 mg, 0.5 mmol) according to , the same method as that of Example360, the title compound was obtained as colorless crystals (217 mg)having a melting point of 138 to 140° C. (dec). elementary analysis asC₂₄H₂₇ClN₂O₂.C₄H₆O₄ calculation value: C, 63.57; H, 6.29; N, 5.30.experimental value: C, 63.37; H, 6.20; N, 5.10.

Example 3798-(5-{[2-(2-Chlophenyl)ethyl]amide}pentanoyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-onemethanesulfonate

Using8-(5-{[2-(2-chlorophenyl)ethyl]amino}pentanoyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-onehydrochloride (205 mg, 0,5 mmol) obtained in Example 39 andmethanesulfonic acid (48 mg, 0.5 mmol) according to the same method asthat of Example 360, the title compound was obtained as colorlesscrystals (213 mg) having a melting point of 186 to 188° C. (dec).elementary analysis as C₂₄H₂₇ClN₂O₂CH₄O₃S calculation value: C, 59.22;H, 6.16; N, 5.52. experimental value: C, 59.07; H, 6.25; N, 5.35.

Example 3808-(5-{[2-(2-Chlophenyl)ethyl]amino}pentanoyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-oneL(±)-tartarate

Using8-(5-{[2-(2-chlorophenyl)ethyl]amino}pentanoyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-onehydrochloride (205 mg, 0,5mmol) obtained in Example 39and L(±)-tartaricacid (75 mg, 0.5 mmol) according to the same method as that of Example360, the title compound was obtained as colorless crystals (225 mg)having a melting point of 103 to 105° C. (dec).

Example 3818-(5-{[2-(2-Chlorophenyl)ethyl]amino}pentanoyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-oneoxalate

Using8-(5-{[2-(2-chlorophenyl)ethyl]amino}pentanoyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-onehydrochloride (205 mg, 0.5 mmol) obtained in Example 39 and oxalic acid(45 mg, 0.5 mmol) according to the same method as that of Example 360,the title compound was obtained as colorless crystals (221 mg) having amelting point of 161 to 163° C. (dec). elementary analysis asC₂₄H₂₇ClN₂O₂.C₂H₂O₄ calculation value: C, 62.33; H, 5.83; N, 5.59.experimental value: C, 62.15; H, 6.00; N, 5.44.

Example 3825-(5-{[2-(2-Chlophenyl)ethyl]amino}pentanoyl)-1,3-dimethyl-1,3-dihydro-2H-benzimidazol-2-onep-toluenesulfonate

Using5-(5-{[2-(2-chlorophenyl)ethyl]amino}pentanoyl)-1,3-dimethyl-1,3-dihydro-2H-benzimidazol-2-onehydrochloride (458 mg, 1.05 mmol) obtained in Example 143 andp-toluenesulfonic acid (200 mg, 1.05 mmol) according to the same methodas that of Example 360, the title compound was obtained as colorlesscrystals (566 mg) having a melting point of 148 to 150° C.

¹H NMR (200 MHz, DMSO-d₆) δ 1.69 (4H, br), 2.28 (3H, s), 3.09 (8H, m),3.38 (3H, s), 3.39 (3H, s), 7.10 (2H, d, J=8.0 Hz), 7.25–7.51 (7H, m),7.73 (1H, s), 7.81 (1H, d, J=7.6 Hz), 8.52 (2H, br). elementary analysisas C₂₂H₂₆ClN₃O₂.C₇H₈O₃S calculation value: C, 60.88; H, 5.99; N, 7.34.experimental value: C, 60.95; H, 6.00; N, 7.47.

Example 3835-(5-{[2-(2-Chlorophenyl)ethyl]amino}pentanoyl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-onehydrochloride

Using tert-butyl2-(2-chlorophenyl)ethyl[5-(1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-5-oxopentyl]carbamate(500 mg) obtained in Reference Example 218 according to the same methodas that of Example 1, the title compound was obtained as colorlesscrystals (340 mg) having a melting point of 192 to 193° C.

¹H NMR (400 MHz, DMSO-d₆) δ 1.67–1.73 (4H, m), 2.97 (2H, br.s), 3.04(2H, t, J=6.7 Hz), 3.11 (4H, br.s), 3.31 (3H, s), 7.18 (1H, d, J=8.3Hz), 7.27–7.34 (2H, m), 7.39 (1H, dd, J=7.0, 2.0 Hz), 7.44 (1H, dd,J=7.0, 2.0 Hz), 7.52 (1H, d, J=1.7 Hz), 7.76 (1H, dd, J=8.3, 1.7 Hz),9.20 (2H, br.s) 11.19 (1H, s). IR (KBr) νcm⁻¹: 3432, 2776, 1749, 1666,1630, 1487, 1319, 1272, 808, 750.

Example 3846-(5-{[2-(2-Chlorophenyl)ethyl]amino}pentanoyl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-onehydrochloride

Using tert-butyl2-(2-chlorophenyl)ethyl[5-(3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-5-oxopentyl]carbamate(500 mg) obtained in Reference Example 218 according to the same methodas that of Example 1, the title compound was obtained as colorlesscrystals (354 mg) having a melting point of 127 to 129° C.

¹H NMR (400 MHz, DMSO-d₆) δ 1.68–1.74 (4H, m), 2.98(2H, br.s), 3.07 (2H,t, J=6.8 Hz), 3.11 (4H, br.s), 3.33 (3H, s), 7.06 (1H, d, J=8.3 Hz),7.27–7.34 (2H, m), 7.39 (1H, dd, J=7.0, 2.0 Hz), 7.44 (1H, dd, J=7.0,2.0 Hz), 7.67 (1H, d, J=1.7 Hz), 7.72 (1H, dd, J=8.3, 1.7 Hz), 9.24 (2H,br.s), 11.32 (1H, s). IR (KBr) νcm⁻¹: 3356, 2733, 1703, 1677, 1623,1474, 1370, 1252, 1181, 757, 691.

Example 3855-(5-{[2-(2-Chloro-4-hydroxyphenyl)ethyl]amino}pentanoyl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-onehydrochloride

Using tert-butyl2-(2-chloro-4-hydroxyphenyl)ethyl[5-(1-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-5-oxopentyl]carbamate(400 mg) obtained in Reference Example 219 according to the same methodas that of Example 1, the title compound was obtained as colorlesscrystals (330 mg) having a melting point of 202 to 204° C.

¹H NMR (400 MHz, DMSO-d₆) δ 1.66–1.68 (4H, m), 2.95–3.06 (8H, m), 3.31(3H, s), 6.78 (1H, dd, J=8.3, 2.4 Hz), 6.85 (1H, d, J=2.4 Hz), 7.16 (1H,d, J=8.3 Hz), 7.18 (1H, d, J=8.3 Hz), 7.52 (1H, d, J=1.5 Hz), 7.76 (1H,dd, J=8.3, 1.5 Hz), 8.96 (2H, br.s), 9.92 (1H, s), 11.16 (1H, s). IR(KBr) νcm⁻¹: 3206, 1703, 1665, 1622, 1502, 1438, 1310, 1083, 705.

Example 3866-(5-{[2-(2-Chloro-4-hydroxyphenyl)ethyl]amino}pentanoyl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-onehydrochloride

Using tert-butyl2-(2-chloro-4-hydroxyphenyl)ethyl[5-(3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-5-oxopentyl]carbamate(250 mg) obtained in Reference Example 219 according to the same methodas that of Example 1, the title compound was obtained as colorlesscrystals (202 mg) having a melting point of 201 to 203° C.

¹H NMR (400 MHz, DMSO-d₆) δ 1.67–1.68 (4H, m), 2.97–3.08 (8H, m), 3.33(3H, s), 6.73 (1H, dd, J=8.3, 2.4 Hz), 6.85 (1H, d, J=2.4 Hz), 7.06 (1H,d, J=8.1 Hz), 7.16 (1H, d, J=8.3 Hz), 7.67 (1H, d, J=1.7 Hz), 7.72 (1H,dd, J=8.1, 1.7 Hz), 8.97 (2H, br.s), 9.92 (1H, s), 11.30 (1H, s). IR(KBr) νcm⁻¹: 3120, 2946, 2797, 1695, 1673, 1612, 1502, 1469, 1180, 691.

Example 3875-(5-{[2-(2-Chloro-4-hydroxyphenyl)ethyl]amino}pentanoyl)-1,3-dimethyl-1,3-dihydro-2H-benzimidazol-2-onehydrochloride

Using tert-butyl2-(2-chloro-4-hydroxyphenyl)ethyl[5-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-5-oxopentyl]carbamate(260 mg) obtained in Reference Example 220 according to the same methodas that of Example 1, the title compound was obtained as colorlesscrystals (212 mg) having a melting point of 195 to 197° C.

¹H NMR (400 MHz, DMSO-d₆) δ 1.67–1.70 (4H, m), 2.97–3.00 (6H, m), 3.09(2H, t, J=6.6 Hz), 3.36 (3H, s), 3.38 (3H, s), 6.73 (1H, dd, J=8.3, 2.4Hz), 6.85 (1H, d, J=2.4 Hz), 7.16 (1H, d, J=8.3 Hz), 7.25 (1H, d, J=8.3Hz), 7.72 (1H, d, J=1.7 Hz), 7.80 (1H, dd, J=8.3, 1.7 Hz), 8.99 (2H,br.s), 9.92 (1H, s). IR (KBr) νcm⁻¹: 3091, 2951, 2780, 1707, 1675, 1622,1501, 1461, 1251, 1190.

Example 3885-[[2-(2-Chlorophenyl)ethyl](methyl)amino]-1-(1-methyl-2,2-dioxide-5,6-dihydro-1H,4H-[1,2,5]thiadiazolo[4,3,2-ij]quinolin-8-yl)-1-pentanonehydrochloride

Using 5-chloro-1-(1-methyl-2, 2-dioxide-5,6-dihydro-1H,4H-[1,2,5]thiadiazolo [4,3,2-ij ]quinolin-8-yl)-1-pentanoneobtained in Reference Example 222 andN-[2-(2-chlorophenyl)ethyl]-N-methylamine according to the same methodas that of Example 9, the title compound was obtained as amorphouspowders.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.53–1.78 (4H, m), 2.19 (2H,quintet, J=6.0 Hz), 2.34 (3H, s), 2.48 (2H, t, J=7.4 Hz), 2.63 (2H, m),2.79–2.96 (6H, m), 3.31 (3H, s), 3.76 (2H, t, J=5.4 Hz), 7.11–7.34 (5H,m), 7.44 (1H, s).

Example 3895-[[2-(2-Methoxyphenyl)ethyl](methyl)amino]-1-(1-methyl-2,2-dioxide-5,6-dihydro-1H,4H-[1,2,5]thiadiazolo[4,3,2-ij]quinolin-8-yl)-1-pentanonehydrochloride

Using5-chloro-1-(1-methyl-2,2-dioxide-5,6-dihydro-1H,4H-[1,2,5]thiadiazolo[4,3,2-ij]quinolin-8-yl)-1-pentanoneobtained in Reference Example 222 andN-[2-(2-methoxyphenyl)ethyl]-N-methylamine according to the same methodas that of Example 9, the title compound was obtained as amorphouspowders.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.57–1.79 (4H, m), 2.19 (2H,quintet, J=6.0 Hz), 2.34 (3H, s), 2.49 (2H, t, J=7.0 Hz), 2.60 (2H, m),2.72–2.85 (4H, m), 2.94 (2H, t, J=7.0 Hz), 3.31 (3H, s), 3.76 (2H, t,J=5.4 Hz), 3.81 (3H, s), 6.82–6.91 (2H, m), 7.12–7.28 (3H, m), 7.44 (1H,s).

Example 3905-{[2-(2-Chlorophenyl)ethyl]amino}-1-(1-methyl-2,2-dioxide-5,6-dihydro-1H,4H-[1,2,5]thiadiazolo[4,3,2-ij]quinolin-8-yl)-1-pentanonehydrochloride

Using tert-butyl2-(2-chlorophenyl)ethyl[5-(1-methyl-2,2-dioxide-5,6-dihydro-1H,4H-[1,2,5]thiadiazolo[4,3,2-ij]quinolin-8-yl(-5-oxopentyl)carbamateobtained in Reference Example 223 according to the same method as thatof Reference Example 1, the title compound was obtained as colorlesscrystals having a melting point of 154 to 155° C.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.53–1.78 (4H, m), 2.19 (2H,quintet, J=6.0 Hz), 2.48 (2H, t, J=7.4 Hz), 2.63 (2H, m), 2.79–2.96 (6H,m), 3.31 (3H, s), 3.75 (2H, t, J=5.4 Hz), 4.61 (1H, br), 7.15–7.34 (5H,m), 7.44 (1H, s).

Example 3915-{[2-(2-Chlorophenyl)ethyl]amino}-1-(2,2-dioxide-5,6-dihydro-1H,4H-[1,2,5]thiadiazolo[4,3,2-ij]quinolin-8-yl)-1-pentanone hydrochloride

Using 5-chloro-1-(2,2-dioxide-5,6-dihydro-1H,4H-[1,2,5]thiadiazolo[4,3,2-ij]quinolin-8-yl)-1-pentanone obtained inReference Example 224 and 2-(2-chlorophenyl)ethylamine according to thesame methods as those of Reference Example 19 and Example 1, the titlecompound was obtained as pale yellow crystals having a melting point of125° C. (dec).

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.51–1.79 (4H, m), 2.19 (2H,quintet, J=6.0 Hz), 2.48 (2H, t, J=7.4 Hz), 2.63 (2H, m), 2.78–2.99 (6H,m), 3.75 (2H, t, J=5.4 Hz), 4.61 (1H, br), 7.15–7.34 (5H, m), 7.45 (1H,s), 11.58 (1H, s).

Example 3925-[[2-(2-Chlorophenyl)ethyl](methyl)amino]-1-(2,2-dioxide-3,4-dihydro-1H-2,1,3-benzothiadiazin-6-yl)-1-pentanonehydrochloride

Using5-chloro-1-(2,2-dioxide-3,4-dihydro-1H-2,1,3-benzothiadiazin-6-yl)-1-pentanoneobtained in Reference Example 226 andN-[2-(2-chlorophenyl)ethyl]-N-methylamine according to the same methodas that of Example 9, the title compound was obtained as amorphouspowders.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.55–1.89 (4H, m), 2.53 (3H, s),2.67–2.79 (4H, m), 2.86 (2H, m), 2.98 (2H, m), 4.54 (2H, s), 5.69 (1H,br), 6.60 (1H, d, J=8.0 Hz), 7.13–7.32 (4H, m), 7.47–7.55 (2H, m), 10.81(1H, s).

Example 3931-(2,2-Dioxide-3,4-dihydro-1H-2,1,3-benzothiadiazin-6-yl)-5-[[2-(2-methoxyphenyl)ethyl](methyl)amino]-1-pentanonehydrochloride

Using5-chloro-1-(2,2-dioxide-3,4-dihydro-1H-2,1,3-benzothiadiazin-6-yl)-1-pentanoneobtained in Reference, Example 226 andN-[2-(2-methoxyphenyl)ethyl]-N-methylamine according to the same methodas that of Example 9, the title compound was obtained as colorlessamorphous powders.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.55–1.89 (4H, m), 2.60 (3H, s),2.67–2.79 (4H, m), 2.86 (2H, m), 2.98 (2H, m), 3.76 (3H, s), 4.45 (2H,s), 5.69 (1H, br), 6.54 (1H, d, J=8.0 Hz), 6.77–6.84 (2H, m), 7.09–7.18(2H, m), 7.47–7.55 (2H, m), 10.81 (1H, s).

Example 3945-{[2-(2-Chlorophenyl)ethyl]amino}-1-(2,2-dioxide-3,4-dihydro-1H-2,1,3-benzothiadiazin-6-yl)-1-pentanonehydrochloride

Using5-chloro-1-(2,2-dioxide-3,4-dihydro-1H-2,1,3-benzothiadiazin-6-yl)-1-pentanoneobtained in Reference Example 226 and 2-(2-chlorophenyl)ethylamineaccording to the same method as those of Reference Example 19 andExample 1, the title compound was obtained as colorless crystals havinga melting point of 197 to 199° C.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.54–1.89 (4H, m), 2.67–2.79 (4H,m), 2.86 (2H, m), 2.98 (2H, m), 4.54 (2H, s), 4.63 (1H, br), 5.68 (1H,br), 6.61 (1H, d, J=8.0 Hz), 7.11–7.32 (4H, m), 7.43–7.49 (2H, m), 10.82(1H, s).

Example 3955-[[2-(2-Chlorophenyl)ethyl](methyl)amino]-1-(1,3-dimethyl-2,2-dioxide-3,4-dihydro-1H-2,1,3-benzothiadiazin-6-yl)-1-pentanonehydrochloride

Using5-chloro-1-(1,3-dimethyl-2,2-dioxide-3,4-dihydro-1H-2,1,3-benzothiadiazin-6-yl)-1-pentanoneobtained in Reference Example 228 andN-[2-(2-chlorophenyl)ethyl]-N-methylamine according to the same methodas that of Example 9, the title compound was obtained as colorlessamorphous powders.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.53–1.79 (4H, m), 2.34 (3H, s),2.48 (2H, t, J=7.0 Hz), 2.61 (2H, m), 2.77 (3H, s), 2.87–2.97 (4H, m),3.39 (3H, s), 4.69 (2H, s), 6.92 (1H, d, J=8.8 Hz), 7.11–7.34 (4H, m),7.74 (1H, d, J=1.8 Hz), 7.91 (1H, dd, J=8.8, 2.2 Hz).

Example 3961-(1,3-Dimethyl-2,2-dioxide-3,4-dihydro-1H-2,1,3-benzothiadiazin-6-yl)-5-[[2-(2-methoxyphenyl)ethyl](methyl)amino]-1-pentanonehydrochloride

Using5-chloro-1-(1,3-dimethyl-2,2-dioxide-3,4-dihydro-1H-2,1,3-benzothiadiazin-6-yl)-1-pentanoneobtained in Reference Example 228 andN-[2-(2-methoxyphenyl)ethyl]-N-methylamine according to the same methodas that of Example 9, the title compound was obtained as colorlessamorphous powders.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.55–1.80 (4H, m), 2.33 (3H, s),2.48 (2H, t, J=7.0 Hz), 2.58 (2H, m), 2.76 (3H, s), 2.80 (2H, m), 2.95(2H, t, J=6.6 Hz), 3.39 (3H, s), 3.81 (3H, s), 4.68 (2H, s), 6.82–6.94(3H, m), 7.12–7.21 (2H, m), 7.74 (1H, d, J=1.8 Hz), 7.92 (1H, dd, J=8.4,1.8 Hz).

Example 3975-{[2-(2-Chlorophenyl)ethyl]amino}-1-(1,3-dimethyl-2,2-dioxide-3,4-dihydro-1H-2,1,3-benzothiadiazin-6-yl)-1-pentanonehydrochloride

Using5-chloro-1-(1,3-dimethyl-2,2-dioxide-3,4-dihydro-1H-2,1,3-benzothiadiazin-6-yl)-1-pentanoneobtained in Reference Example 228 and 2-(2-chlorophenyl)ethylamineaccording to the same method as those of Reference Example 19 andExample 1, the title compound was obtained as colorless crystals havinga melting point of 164 to 165° C.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.51–1.76 (4H, m), 2.48 (2H, t,J=7.0 Hz), 2.61 (2H, m), 2.77 (3H, s), 2.87–2.97 (4H, m), 3.39 (3H, s),3.92 (1H, br), 4.69 (2H, s), 6.92 (1H, d, J=8.8 Hz), 7.11–7.34 (4H, m),7.74 (1H, s), 7.91 (1H, d, J=8.8 Hz).

Example 3985-{5-[[2-(2-Chlorophenyl)ethyl](methyl)amino]pentanoyl}-2-methyl-1H-isoindole-1,3(2H)-dionehydrochloride

Using 5-(5-chloropentanoyl)-2-methyl-1H-isoindole-1,3(2H)-dione obtainedin Reference Example 231 and N-[2-(2-chlorophenyl)ethyl]-N-methylamineaccording to the same method as that of Example 9, the title compoundwas obtained as colorless amorphous powders.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.55–1.89 (4H, m), 2.34 (3H, s),2.49 (2H, t, J=7.0 Hz), 2.61 (2H, m), 2.86–2.97 (2H, m), 3.05 (2H, t,J=7.0 Hz), 3.22 (3H, s), 7.10–7.33 (4H, m), 7.94 (1H, d, J=7.8 Hz), 8.29(1H, d, J=8.4 Hz), 8.37 (1H, s).

Example 3995-{5-[[2-(2-Methoxyphenyl)ethyl](methyl)amino]pentanoyl}-2-methyl-1H-isoindole-1,3(2H)-dionehydrochloride

Using 5-(5-chloropentanoyl)-2-methyl-1H-isoindole-1,3(2H)-dione obtainedin Reference Example 231 and N-[2-(2-methoxyphenyl)ethyl]-N-methylamineaccording to the same method as that of Example 9, the title compoundwas obtained as colorless amorphous powders.

¹H NMR (free, base; 200 MHz, CDCl₃) δ 1.56–1.87 (4H, m), 2.33 (3H, s),2.49 (2H, t, J=7.0 Hz), 2.61 (2H, m), 2.71–2.82 (2H, m), 3.05, (2H, t,J=6.8 Hz), 3.21 (3H, s), 3.82 (3H, s), 6.85 (2H, t, J=8.6 Hz), 7.13 (2H,d, J=7.4 Hz), 7.93 (1H, d, J=7.8 Hz), 8.30 (1H, d, J=8.4 Hz), 8.37. (1H,s).

Example 400N-(5-{5-[[2-(2-Chlorophenyl)ethyl](methyl)amino]pentanoyl}-2,3-dihydro-1H-inden-2-yl)acetamidehydrochloride

Using N-[5-(5-chloropentanoyl)-2,3-dihydro-1H-inden-2-yl]acetamideobtained in Reference Example 232 andN-[2-(2-chlorophenyl)ethyl]-N-methylamine according to the same methodas that of Example 9, the title compound was obtained as colorlessamorphous powders.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.53–1.78 (4H, m), 1.94 (3H, s),2.34 (3H, s), 2.48 (2H, t, J=7.4 Hz), 2.60 (2H, m), 2.78–2.98 (6H, m),3.31 (2H, dd, J=16.4, 6.8 Hz), 4.74 (1H, m), 5.96 (1H, d, J=7.2 Hz),7.09–7.34 (5H, m), 7.78 (2H, m).

Example 401N-(5-{5-[[2-(2-Methoxyphenyl)ethyl](methyl)amino]pentanoyl}-2,3-dihydro-1H-inden-2-yl)acetamidehydrochloride

Using N-[5-(5-chloropentanoyl)-2,3-dihydro-1H-inden-2-yl]acetamideobtained in Reference Example 232 andN-[2-(2-methoxyphenyl)ethyl]-N-methylamine according to the same methodas that of Example 9, the title compound was obtained as colorlessamorphous powders.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.56–1.78 (4H, m), 1.94 (3H, s),2.33 (3H, s), 2.48 (2H, t, J=7.4 Hz), 2.60 (2H, m), 2.78–2.98 (6H, m),3.31 (2H, dd, J=16.4, 6.8 Hz), 3.81 (3H, s), 4.74 (1H, m), 6.04 (1H, d,J=7.2 Hz), 6.81–6.90 (2H, m), 7.11–7.30 (3H, m), 7.78 (2H, m).

Example 402N-[5-(5-{[2-(2-Chlorophenyl)ethyl]amino}pentanoyl)-2,3-dihydro-1H-inden-2-yl]acetamidehydrochloride

Using N-[5-(5-chloropentanoyl)-2,3-dihydro-1H-inden-2-yl]acetamideobtained in Reference Example 232 and 2-(2-chlorophenyl)ethylamineaccording to the same methods as those of Reference Example 19 andExample 1, the title compound was obtained as colorless crystals havinga melting point of 150 to 151° C.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.53–1.78 (4H, m), 1.94 (3H, s),2.48, (2H, t, J=7.4 Hz), 2.60 (2H, m), 2.78–2.98 (6H, m), 3.31 (2H, dd,J=16.4, 6.8 Hz), 4.53 (1H, br), 4.74 (1H, m), 5.96 (1H, d, J=7.2 Hz),7.09–7.34 (5H, m), 7.78 (2H, m).

Example 4035-(5-{[2-(2-Chlorophenyl)ethyl]amino}-1-hydroxypentyl)-1,3-dimethyl-1,3-dihydro-2H-benzimidazol-2-onehydrochloride

Using tert-butyl2-(2-chlorophenyl)ethyl[5-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-5-hydroxypentyl]carbamate(1.25 g) obtained in Reference Example 235 according to the same methodas that of Example 1, the title compound was obtained as colorlesscrystals (340 mg) having a melting point of 253 to 255° C.

¹H NMR (400 MHz, CD₃OD) δ 1.32–1.41 (1H, m), 1.46–1.57 (1H, m),1.68–1.75 (3H, m), 1.83–1.92 (1H, m), 3.01 (2H, t, J=7.8 Hz), 3.12–3.23(4H, m), 3.40 (3H, s), 3.41 (3H, s), 4.21–4.24 (1H, m), 4.91 (3H, s),7.08–7.12 (3H, m), 7.27–7.31 (2H, m), 7.37–7.42 (2H, m). IR (KBr) νcm⁻¹:3428, 2944, 1712, 1510, 1462, 747, 584.

Example 4048-(5-{[2-(2-Chloro-4-hydroxyphenyl)ethyl]amino}pentanoyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-onehydrochloride

Using tert-butyl2-(2-chloro-4-hydroxyphenyl)ethyl[5-oxo-5-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)pentyl]carbamate(240 mg) obtained in Reference Example 236 according to the same methodas that of Example 1, the title compound was obtained as colorlesscrystals (203 mg) having a melting point of 184 to 185° C.

Example 4051-(1-Acetyl-2,3-dihydro-1H-indol-5-yl)-5-{[2-(2-chloro-4-hydroxyphenyl)ethyl]amino}pentan-4-onehydrochloride

Using tert-butyl5-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-5-oxopentyl[2-(2-chloro-4-hydroxyphenyl)ethyl]carbamate(320 mg) obtained in Reference Example237 according to the same methodas that of Example 1, the title compound was obtained as colorlesscrystals (260 mg) having a melting point of 197 to 199° C.

¹H NMR (400 MHz, DMSO-d₆) δ 1.64–1.79 (4H, m), 2.17 (3H, s), 2.93–3.01(8H, m), 3.16 (2H, t, J=8.3 Hz), 4.13 (2H, t, J=8.3 Hz), 6.73 (1H, dd,J=8.3, 2.4 Hz), 6.87 (1H, d, J=2.4 Hz), 7.15 (1H, d, J=8.3 Hz), 7.81(1H, s),7.82 (1H, d, J=8.3 Hz), 8.07 (1H, d, J=8.3 Hz), 9.18 (2H, s),9.51 (1H, br). IR (KBr) νcm⁻¹: 2949, 2780, 1686, 1.632, 1587, 1503,1443, 1405, 1248, 826.

Example 4068-(5-{[2-(2-Chloro-4-hydroxyphenyl)ethyl]amino}pentanoyl)-1-methyl-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-onehydrochloride

Using tert-butyl2-(2-chloro-4-hydroxyphenyl)ethyl[5-(1-methyl-2-oxo-1,2,5,6-tetrahydro-4H-imidazo[4,5,1-ij]quinolin-8-yl)-5-oxopentyl]carbamate(114 mg) obtained in Reference Example 238 according to the same methodas that of Example 1, the title compound was obtained as colorlesscrystals (82 mg) having a melting point of 175 to 177° C.

¹H NMR (400 MHz, DMSO-d₆) δ 1.68 (4H, br.s), 2.00–2.04 (2H, m),2.98–3.07 (8H, m), 3.34, (2H, br.s), 3.36 (3H, s), 3.71–3.76 (2H, m),6.73 (1H, dd, J=8.5, 2.4 Hz), 6.85 (1H, d, J=2.4 Hz), 7.16 (1H, d, J=8.5Hz), 7.59 (2H, s), 9.00 (2H, br.), 9.93 (1H, s) IR (KBr) νcm⁻¹: 3426,2955, 2790, 1698, 1641, 1610, 1501, 1436, 1277, 1251.

Example 4078-(5-{[2-(2-Chloro-4-hydroxyphenyl)ethyl]amino}pentanoyl)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-onehydrochloride

Using tert-butyl2-(2-chloro-4-hydroxyphenyl)ethyl[5-oxo-5-(2-oxo-1,2,5,6-tetrahydro-4H-imidazo[4,5,1-ij]quinolin-8-yl)pentyl]carbamate(55 mg) obtained in Reference Example 239 according to the same methodas that of Example 1, the title compound was obtained as colorlesscrystals (38 mg) having a melting point of 185 to 186° C.

¹H NMR (400 MHz, DMSO-d₆) δ 1.66 (4H, br.s), 2.00–2.03 (2H, m), 2.82(2H, t, J=6.0 Hz), 2.97–3.02 (8H, m), 3.42 (1H, br.), 3.71 (2H, t, J=6.0Hz), 6.73 (1H, dd, J=8.3, 2.2 Hz), 6.85 (1H, d, J=2.2 Hz), 7.16 (1H, d,J=8.3 Hz), 7.38 (1H, s), 7.55 (1H, s), 8.91 (2H, br.s), 9.91 (1H, s). IR(KBr) νcm⁻¹: 3252, 2959, 2815, 1717, 1664, 1613, 1502, 1439, 1150, 668.

Example 4089-(5-{[2-(2-Chloro-4-hydroxyphenyl)ethyl]amino}pentanoyl)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-onehydrochloride

Using tert-butyl2-(2-chloro-4-hydroxyphenyl)ethyl]-5-oxo-5-(2-oxo-1,2,5,6-tetrahydro-4H-imidazo[4,5,1-ij]quinolin-9-yl)pentyl]carbamate(64 mg) obtained in Reference Example 240 according to the same methodas that of Example 1, the title compound was obtained as colorlesscrystals (44 mg) having a melting point of 173 to 175° C.

¹H NMR (400 MHz, DMSO-d₆) δ 1.68 (4H, br.s), 1.99–2.02 (2H, m), 2.82(2H, t, J=6.0 Hz), 2.97–3.03 (8H, m), 3.71, (2H, t, J=6.0 Hz), 4.24 (1H,br.), 6.73, (1H, dd, J=8.3, 2.4 Hz), 6.85 (1H, d, J=2.4 Hz), 6.91 (1H,d, J=8.3 Hz), 7.16 (1H, d, J=8.0 Hz), 7.53 (1H, d, J=8.0 Hz), 8.90, (2H,br.s), 10.82 (1H, s). IR (KBr) νcm⁻¹: 3152, 2958, 1689, 1610, 1502,1488, 1442, 1229, 1041, 692.

Example 409N-(5-{5-[[2-(2-Chlorophenyl)ethyl](methyl)amino]pentanoyl}-2,3-dihydro-1H-inden-2-yl)acetamidehydrochloride

Using N-[5-(5-Chloropentanoyl)-2,3-dihydro-1H-inden-2-yl]acetamideobtained in Reference Example 241 andN-[2-(2-chlorophenyl)ethyl]-N-methylamine according to the same methodas that of Example 9, the title compound was obtained as colorlessamorphous powders.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.53–1.80 (4H, m), 2.15 (3H, s),2.34 (3H, s), 2.48 (2H, t, J=7.4 Hz), 2.61 (2H, m), 2.81 (3H, s),2.85–2.98 (6H, m), 3.18 (2H, dd, J=16.4, 6.8 Hz), 5.32 (1H, m),7.08–7.38 (5H, m), 7.78 (2H, m).

Example 410N-(5-{5-[[2-(2-Methoxyphenyl)ethyl](methyl)amino]pentanoyl}-2,3-dihydro-1H-inden-2-yl)acetamidehydrochloride

Using N-[5-(5-chloropentanoyl)-2,3-dihydro-1H-inden-2-yl]acetamideobtained in Reference Example 241 andN-[2-(2-Methoxyphenyl)ethyl]-N-methylamine according to the same methodas that of Example 9, the title compound was obtained as colorlessamorphous powders.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.55–1.80 (4H, m), 2.15 (3H, s),2.34 (3H, s), 2.47 (2H, t, J=7.2 Hz), 2.58 (2H, m), 2.72–2.82 (4H, m),2.80 (3H, s), 2.96 (2H, t, J=7.0 Hz), 3.25 (2H, dd, J=17.0, 8.8 Hz),3.80 (3H, s), 5.25 (1H, m), 6.80–6.88 (2H, m), 7.11–7.18 (2H, m), 7.28(1H, m), 7.79 (2H, m).

Example 411N-[5-(5-{[2-(2-Chlorophenyl)ethyl]amino}pentanoyl)-2,3-dihydro-1H-inden-2-yl]acetamidehydrochloride

Using N-[5-(5-chloropentanoyl)-2,3-dihydro-1H-inden-2-yl]acetamideobtained in Reference Example 241 and 2-(2-chlorophenyl)ethylamineaccording to the same methods as those of Reference Example 19 andExample 1, the title compound was obtained as colorless crystals havinga melting point of 137 to 138° C.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.53–1.79 (4H, m), 2.15, (3H, s),2.48 (2H, t, J=7.4 Hz), 2.61 (2H, m), 2.81 (3H, s), 2.85–2.98 (6H, m),3.18 (2H, dd, J=16.4, 6.8 Hz), 4.28 (1H, br), 5.32 (1H, m), 7.09–7.37(5H, m), 7.78 (2H, m).

Example 412N-(5-{5-[[2-(2-Chlorophenyl)ethyl](methyl)amino]pentanoyl}-2,3-dihydro-1H-inden-2-yl)methanesulfonamidehydrochloride

UsingN-[5-(5-chloropentanoyl)-2,3-dihydro-1H-inden-2-yl]methanesulfonamideobtained in Reference Example 242 andN-[2-(2-chlorophenyl)ethyl]-N-methylamine according to the same methodas that of Example 9, the title compound was obtained as colorlessamorphous powders.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.55–1.77 (4H, m), 2.34 (3H, s),2.48 (2H, t, J=7.6 Hz), 2.61, (2H, m), 2.71 (3H, s), 2.89 (3H, s),2.91–3.10 (6H, m), 3.35 (2H, dd, J=16.8, 8.4 Hz), 4.90 (1H, quint, J=7.0Hz), 7.09–7.32 (5H, m), 7.78, (2H, m).

Example 413N-(5-{5-[[2-(2-Methoxyphenyl)ethyl](methyl)amino]pentanoyl}-2,3-dihydro-1H-inden-2-yl)methanesulfonamidehydrochloride

UsingN-[5-(5-chloropentanoyl)-2,3-dihydro-1H-inden-2-yl]methanesulfonamideobtained in Reference Example 242 andN-[2-(2-methoxyphenyl)ethyl]-N-methylamine according to the same methodas that of Example 9, the title compound was obtained as colorlessamorphous powders.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.54–1.79 (4H, m), 2.33 (3H, s),2.48 (2H, t, J=7.0 Hz), 2.58 (2H, m), 2.71 (3H, s), 2.80 (2H, m), 2.89(3H, s), 2.96 (2H, m), 3.05 (2H, m), 3.28 (2H, dd, J=16.4, 8.0 Hz), 3.81(3H, s), 4.91 (1H, m), 6.81–6.90 (2H, m), 7.12–7.31 (3H, m), 7.78 (2H,m).

Example 414N-[5-(5-{[2-(2-Chlorophenyl)ethyl]amino}pentanoyl)-2,3-dihydro-1H-inden-2-yl]methanesulfonamidehydrochloride

UsingN-[5-(5-chloropentanoyl)-2,3-dihydro-1H-inden-2-yl]methanesulfonamideobtained in Reference Example-242 and 2-(2-chlorophenyl)ethylamineaccording to the same methods as those of Reference Example 19 andExample 1, the title compound was obtained as colorless amorphouspowders.

¹H NMR (free base; 200 MHz, CDCl₃) δ 1.55–1.77 (4H, m), 2.47 (2H, t,J=7.4 Hz), 2.61 (2H, m), 2.71 (3H, s), 2.89 (3H, s), 2.91–3.10 (6H, m),3.35 (2H, dd, J=16.4, 8.0 Hz), 4.08 (1H, br), 4.90 (1H, quint, J=7.0Hz), 7.09–7.32 (5H, m), 7.78 (2H, m).

Preparation Example 1

-   (1) Compound of Example 20: 1 g-   (2) Lactose: 197 g-   (3) Corn starch: 50 g-   (4) Magnesium stearate: 2 g

The (1), (2) and corn starch (20 g) were kneaded, and the mixturetogether with a paste made of corn starch (15 g) and 25 mL of water wasgranulated, and corn starch (15 g) and the (4) were added thereto. Themixture was compressed with a compression tabletting machine to give2000 tablets having a diameter of 3 mm containing 0.5 mg of the compoundof Example 20 per tablet.

Preparation Example 2

-   (1) Compound of Example 20: 2 g-   (2) Lactose: 197 g-   (3) Corn starch: 50 g-   (4) Magnesium stearate: 2 g

According to the same method as that of Preparation Example 1, 2000tablets having a diameter of 3 mm containing 1.0 mg of the compound ofExample 20 per tablet were prepared.

Preparation Example 3

-   (1) Compound of Example 20: 5.0 mg-   (2) Lactose: 60.0 mg-   (3) Corn starch: 35.0 mg-   (4) Gelatin: 3.0 mg-   (5) Magnesium stearate: 2.0 mg

A mixture of the (1), (2) and (3) was granulated by passing through a 1mm mesh sieve using 0.03 ml of a 10% aqueous gelatin solution (3.0 mg interms of gelatin), and the granule was dried at 40° C., and then passedthrough a sieve again. The resulting granule was mixed with the (5), andcompressed. The resulting central tablet was coated with a sugar coatingcomposed of a suspension containing sucrose, titanium dioxide, talc andgum arabic in water. The coated tablet was given luster with beewax togive a coated tablet.

Experimental Example 1

a) Measurement of Acetylcholinesterase Inhibitory Activity

Acetylcholinesterase inhibitory activity of Example compounds wasmeasured using human erythrocyte-derived acetylcholinesterase by anacetylthiocholine method (Ellman method).

Human erythrocyte-drived acetylcholinesterase (Sigma) was dissolved indistilled water to the concentration of 0.2 IU/mL to obtain an enzymespecimen. 20 μL of a drug solution, 30 μL of 80 mM Tris-HCL (pH 7.4), 50μL of an enzyme specimen and 50 μL of 5 mM 5,5-dithio-bis(2-nitrobenzoic acid)(Sigma) were dispensed on a 96-well microplate, andthis was shaken for 10 seconds. 50 μL of 4 mM acetylthiocholine iodide(Sigma) was added, this was shaken again and, immediately after,increase in absorbance at 414 nM was measured at 30 second intervals for10 minutes. Enzyme activity was measured by the following equation:R=5.74×10⁻⁷×Δ_(A)(wherein R represents enzyme activity (mol), and Δ_(A) representsincrease in absorbance at 414 nM)

Regarding each compound, the experiment was repeated at least threetimes to obtain 50% inhibition concentration (IC₅₀). According to thesimilar method to the above-mentioned acetylcholinesterase inhibitoryactivity of distigmine which is a known acetylcholinesterase inhibitorwas measured.

b) Measurement of α_(1A) Receptor Binding Inhibitory Activity

The following gene manipulation method was carried out according to themethod described in a textbook (Miniatis et al., Molecular Cloning, ColdSpring Harbor Laboratory, 1989) or the method described in protocolattached to a reagent.

(i) Preparation of Expression Plasmid for Human Adrenaline α_(1A)Receptor

An adrenaline α_(1A) receptor gene was cloned from a human liver cDNA bya PCR method. A PCR reaction was performed with Gene Amp PCR System 9700(Applied Biosystems) using 200 ng of a human liver cDNA library (TAKARASHUZO Co., Ltd.) as a template and using TaKaRa Pyrobest DNA Polymerase(TAKARA SHUZO CO., Ltd) and adding each 50 pmol of a primer set5′-CCGAATTCGGCTGGGACCATGGTGTTTCTC-3′ [SEQ ID No.: 1] and5′-CTGTCGACCTTTCCTGTCCTAGACTTCCTC-3′[SEQ ID No.: 2] prepared makingreference to a nucleotide sequence of an adrenaline α_(1A) receptor genewhich was reported by Hirasawa A. et al. (Biochem. Biophys. Res.Commun.,195, 902–909(1993)) (reaction condition: 45 cycles of 15 seconds at 94°C., and 3 minutes 30 seconds at 68° C.).

The obtained PCR fragment was digested with restriction enzymes Eco RI(TAKARA SHUZO Co. Ltd.) and Sal I (TAKARA SHUZO Co. Ltd.), and agarosegel electrophoresis was performed to recover DNA fragments. The DNAfragments were mixed with an animal cell expression plasmid pMSR αneo(Administration No. A99–0013) which had been digested with Eco RI andSal I, ligated with DNA Ligation Kit Ver.2 (TAKARA SHUZO Co. Ltd.), anda competent cell of Esherichia coli JM109 was transformed to obtain aplasmid pMSR αneoA dreα_(1A).

(ii) Introduction of Plasmid for Expression of Human Adrenaline α_(1A)Receptor into CHO-K1 Cell and Preparation of Membrane Fraction

CHO-K1 cells which had been subcultured in a 150 cm² culturing flask(Corning Coaster) using Ham F12 medium (Invitrogen) containing 10% fetalbovine serum (TRACE SCIENTIFIC) was peeled with 0.5 g/L trypsin-0.2 g/LEDTA(Invitrogen), cells were washed with D-PBS(−) (Invitrogen),centrifuged (1000 rpm, 5 min), and suspended in D-PBS(−). Then, a DNAwas introduced into cells using a gene pulser (BioRad) according to thefollowing conditions. That is, 1×10⁷ cells and 10 μg of pMSR αneo-Adreα_(1A) suspended in 700 μl of D-PBS(−) were added to a cuvette(BioRad) having a 0.4 cm gap, and electroporation was performed at avoltage of 0.25 kV, and capacitance of 960 μF. Thereafter, cells weretransferred to Ham F12 medium containing 10% fetal bovine serum and,after cultured for 24 hours, cells were peeled again, centrifuged,seeded on a 96-well plate (Corning) at 1000/well and cultured for 10days using Ham F12 medium containing 10% fetal bovine serum and 500μg/ml geneticine (Invitrogen), thereby, a geneticine-resistant strainwas obtained.

A plurality of the thus obtained geneticine-resistant strains wereselected, each strain was cultured in a cell culturing flask (150 cm²)to semiconfluent, and a cell membrane fraction was prepared as follows:

Semiconfluent cells were peeled with D-PBS(−) containing 0.02% EDTA,cells were recovered by centrifugation, cells were suspended in a bufferfor preparing a membrane (50 mM Tris-hydrochloric acid (pH7.5), 1 mMEDTA, 10 mM magnesium chloride, 0.25 mM PMSF, 1 μg/ml pepstatin, 20μg/ml leupeptin, 0.5% BSA), and treated with a Polytron homogenizer(model PT-3000, KINEMATICA AG) three times at 20,000 rpm for 20 secondsto grind cells. After grinding of cells, ground cells were centrifugedat 2000 rpm for 10 minutes to obtain the supernatant containing amembrane fraction. The supernatant was centrifuged with asuper-centrifuge (model L8-70M, rotor 70Ti, Beckmann) at 30,000 rpm for1 hour to give precipitates containing a membrane fraction. Theresulting membrane fraction of each clone was subjected to the followingbinding experiment

A membrane fraction (100 μg/ml) diluted with a buffer for preparing amembrane and [³H]-Prazosin (2.5 nM, NEN Life Science Products) which isa ligand were added to a 96-well microplate to react at room temperaturefor 1 hour. For measuring non-specific binding, Prazosin (Sigma) wasfurther added to 10 μM. Then, the membrane fraction was transferred to aunifilter GF/C (Parkerd) by filtering the reaction solution using a cellharvester (Packerd), and washed with a 50 mM Tris ice-cooled buffer (pH7.5) three times. After the filter was dried, Microsinti 0 (Packerd) wasadded to the filter, and radioactivity was measured with Topcount(Packerd). Using a strain exhibiting the most excellent S/B value (totalbinding radioactivity/non-specific binding radioactivity) in measurementof binding using the membrane fraction, a membrane fraction for thefollowing compound assessment was prepared by the same method as thatdescribed above, and used for the following compound assessment.

(iii) Assessment of Example Compound

A membrane fraction (100 μg/ml) diluted with a buffer for preparing amembrane, the compound and [³H]-Prazosin (2.5 nM, NEN Life ScienceProducts) were added to a 96-well microplate to react at roomtemperature for 1 hour. For measuring non-specific binding, Prazosin(Sigma) which is a cold ligand was added to 10 μM. Then, a membranefraction was transferred to a unifilter GF-C (Packerd) by filtering thereaction solution with cell harvester (Packerd), and washed three timeswith cooled 50 mM Tris buffer (pH 7.5). After drying the filter,Microsinti 0 (Packerd) was added to the filter, and radioactivity wasmeasured with Topcount (Packerd). The concentration (IC₅₀) of thecompound necessary to reduce the binding amount of [³H]-Prazosin to themembrane fraction to 50% was calculated by PRISM 2.01 (GraphpadSoftware). IC₅₀ of urapidil (hydrochloride) which is a known α₁ receptorantagonist was obtained similarly. The results measured by theaforementioned methods a) and b) are shown in the following in Table.

TABLE 1 Compound AchE: IC₅₀ (μM) α_(1A): IC₅₀ (μM) Example 20 0.1790.165 Example 84 0.169 0.236 Distigmine 0.723 — urapidil — 0.357

From the aforementioned results, it turns out that the present Compound(I) has an excellent acetylcholinesterase inhibitory action and, at thesame time, excellent α_(1A) receptor binding inhibitory activity.

Experimental Example 2

a) Effect on Maximum Urine Flow Rate, Bladder Internal Pressure andVoiding Efficiency in Guinea Pigs Loaded with Phenylephrine (PressureFlow Study)

Hartley male guinea pigs (Slc) weighing 300 to 350 g was anesthetizedwith urethane (1.2 g/kg, i.p.), and a median was incised to exposebladder. Two polyethylene tubes were inserted into bladder, and one ofthem was used for injecting a physiological saline and the other wasused for measuring a bladder internal pressure. A cannulae was insertedinto a left femoral vein, and phenylephrine was continuouslyadministered intravenously at 3 μg/animal/min until the completion ofexperiment. A physiological saline was injected into bladder at a rateof 0.3 mL/min, and injection was stopped when urination was confirmed.The urinated urine weight was measured with an electron balance (HX-400,A & D) at real time. Analogue data of bladder internal pressure andurine weight were inputted into an AD transducer (MP-100, BIOPACSystems), and digital signals were analyzed with exclusive analyzingsoftware (AcqKnowledge 3.5.3, BIOPAC Systems). The sampling rate of datawas 10 Hz, and data of urination amount and urine flow rate weresubjected to a lowcut filter at 0.5 Hz in order to remove noises. Thevalue of urine weight was differentiated to calculate urine flow rate(Q), and maximum urine flow rate (Qmax) at urination and bladderinternal pressure (Pves (Qmax)) at maximum urine flow were calculated.The urination weight 1 g was converted into 1 mL to calculate theurination amount, and divided by bladder volume to obtain voidingefficiency (Voiding Efficiency). Example compound was dissolved in DMSO,and the solution was intravenously administered at 0.5 mL/kg. 10 minutesafter administration of test compound, urinary reflection was recordedagain, and change in urine flow rate (ΔQmax), and change in bladderinternal pressure (ΔPves(Qmax)) and voiding efficiency were assessed.The, change in urine flow rate (ΔQmax) and change in bladder internalpressure (ΔPves (Qmax)) were an amount of change (Δvalue) obtained bysubtracting each value before administration of test compound from eachvalue after administration, and voiding efficiency was assessed by arelative value (% of pre-value) of after administration of test compoundrelative to before administration. Tamsulosin which is a known Δ₁receptor antagonist was measured similarly. A significance diffenencewas tested by a Dunnett test by comparing with each value of a vehicle(DMSO)-administered group.

b) Effect on Blood Pressure

Hartley male guinea pigs (Slc) weighing 300 to 350 g was anesthetizedwith urethane (1.2 g/kg), and retained, a cervical region was incised toexpose a left common carotid artery. A polyethylene tube filled withphysiological saline containing heparin (10 U.I./ml) was inserted intoan artery, and blood pressure was measured with a pressure transducer. Acannulae for administering test compound was inserted into a vein at anend of left hind leg, and a test compound dissolved in distilled waterwas administered therethrough at 0.5 mL/kg. The blood pressure wasrecorded at 20 Hz using an analogue data inputting apparatus (MP-100,BIOPAC Systems), and analyzed by analyzing software (AcqKnowledge 3.5.3,BIOPAC Systems). Example compound and tamsulosin were studied for a doseat which effects were recognized in the aforementioned test a (PressureFlow Study), and an average blood pressure just before administration oftest compound and an average blood pressure 15 minutes afteradministration were measured. Data were statistically treated by Pairedt-test.

The results by Pressure Flow Study for the present invention compoundand tamsulosin, and effects on blood pressure were summarized in thefollowing Table.

TABLE 2 Effects of present invention compound and tamsulosin on changein maximum urine flow rate (ΔQmax), change in bladder internal pressure(ΔPves(Qmax)) and voiding efficiency. ΔPves voiding Dose ΔQmax (Qmax)efficiency Compound (mg/ kg, i.v.) (mL/s) (cmH₂O) (%) n Vehicle — −0.029± 0.017  2.27 ± 1.88  82.3 ± 4.0 9 tamsulosin 0.01  0.036 ± 0.014* −3.56± 1.09* 118.5 ± 13.4** 8 Example 20 0.1   0.060 ± 0.016** −1.73 ± 1.54150.1 ± 20.1** 8 *P ≦ 0.05, **P ≦ 0.01

TABLE 3 Effects of present invention compound and tamsulosin on bloodpressure Blood pressure (mmHg) Dose Before After Compound (mg/kg, i.v.)administration administration n tamsulosin 0.01 54.5 ± 2.5 32.9 ± 3.0**6 Example 20 0.1 53.5 ± 3.6 54.6 ± 2.8  6 **: P ≦ 0.01

From the aforementioned results, it turns out that the α₁ receptorantagonist tamsulosin (0.01 mg/kg, i.v.) significantly reduces bladderinternal pressure, and significantly increases maximum urine flow rateand voiding efficiency, but significantly reduces blood pressure byabout 40% at the same dose. On the other hand, it turns out that thepresent invention compound (0.1 mg/kg, i.v.) significantly increasesurine flow rate and voiding efficiency and, at the same time, does notinfluence on blood pressure at the same dose without significantlyreducing bladder internal pressure. From results of the aforementionedExperimental Examples 1 and 2, it is obvious that the present inventioncompound having both of an acetylcholinesterase inhibitory action and anα₁ antagonistic action has excellent effect of preventing or treatingvoiding disturbance, in particular, voiding difficulty.

In addition, by the in vivo assessment method by Pressure Flow Studyusing guinea pigs loaded with phenylephrine shown in the aforementionedExperimental Example 1a, effects of the present invention compound andtamsulosin on maximum urine flow rate and bladder internal pressurecould be properly assessed at the same time. From this, it is obviousthat the present method is useful as a method for assessing atherapeutic agent for voiding disturbance accompanied with benignprostatic hyperplasia.

INDUSTRIAL APPLICABILITY

Since the compound having both an acetylcholinesterase inhibitory actionand an a antagonistic action used in the present invention exhibitsexcellent effect of improving urinary function of bladder (effect ofimproving urine flow rate and voiding efficiency) and, at the same time,does not influence on urinary pressure and a blood pressure, it isuseful as a preventive or therapeutic agent for voiding disturbance.

In addition, the present screening method in which Pressure Flow Studyis applied to an animal model loaded with an α agonist (phenylephrine)is useful as an excellent screening method for a compound having effectof preventing or treating voiding disturbance accompanied with benignprostatic hyperplasia or a salt thereof.

1. A compound represented by the formula:

wherein Ar₁ represents

wherein A ring represents a benzene ring which may have 1 to 4 substituents selected from (i) halogen, (ii) C₁₋₆ alkoxy, (iii) halogenoC₁₋₆ alkoxy, (iv) amino, (v) (mono or di) C₁₋₆ alkylamino, (vi) 1-pyrrolidinyl, (vii) piperidino, (viii) 1-piperazinyl, (ix) N-methyl-1-piperazinyl, (x) N-acetyl-1-piperazinyl, (xi) morpholino, (xii) hexamethyleneimino, (xiii) imidazolyl, (xiv) C₁₋₆ alkyl which may be substituted with carboxy optionally esterified with C₁₋₆ alkyl, (xv) lower alkyl-carbonylamino, (xvi) lower alkylsulfonylamino, (xvii) aminosulfonyl, (xviii) (mono or di) C₁₋₆ alkylaminosulfonyl, (xix) 5- to 7-membered cyclic amino-sulfonyl, (xx) carbamoyl, (xxi) (mono or di) C₁₋₆ alkylcarbamoyl, (xxii) 5- to 7-membered cyclic amino-carbonyl and (xxiii) cyano, L₁ represents a C₄₋₆ alkylene group which may have 1 to 4 substituents selected from halogen atom, nitro, cyano, optionally halogenated C₁₋₆ alkoxy and hydroxy; L₂ represents a C₂₋₄ alkylene group which may have 1 to 4 substituents selected from halogen atom, hydroxy, oxo and phenyl; R represents (i) hydrogen atom, (ii) C₁₋₄ alkyl group which may have 1 to 3 substituents selected from halogen atom and hydroxy or (iii) C₇₋₁₆ aralkyl group; X represents a bond, an oxygen atom or NH; and Ar₂ represents a C₆₋₁₀ aryl group which may have 1 to 5 substituents selected from halogen atom, C₁₋₆ alkyl group, halogenoC₁₋₆ alkyl, hydroxy, C₁₋₆ alkoxy, halogenoC₁₋₆ alkoxy, nitro, amino, cyano, carbamoyl, amino which may be substituted with carbamoyl or formyl, each of which is optionally substituted with C₁₋₆ alkyl, C₁₋₃ alkylenedioxy, aminocarbonyloxy group which may be substituted with C₁₋₆ alkyl, 5- to 7-membered cyclic amino-carbonyloxy, aminosulfonyl, mono-C₁₋₆ alkylaminosulfonyl and di-C₁₋₆ alkylaminosulfonyl, or a salt thereof.
 2. The compound according to claim 1, wherein A ring represents a benzene ring which may have 1 or 2 substituents selected from aminosulfonyl, mono- or di-C₁₋₆ alkylaminosulfonyl, carbamoyl and mono- or di-C₁₋₆ alkyl-carbamoyl, L₁ represents a C₄₋₅ alkylene group, L₂ represents a C₂₋₃ alkylene group which may have as substituents phenyl, hydroxy or oxo, R represents hydrogen atom or C₁₋₄ alkyl group, X represents a bond, an oxygen atom or NH, and Ar₂ represents a C₆₋₁₀ aryl group which may have 1 to 3 substituents selected from halogen atom, nitro, hydroxy, optionally halogenated C₁₋₆ alkyl, optionally halogenated C₁₋₆ alkoxy and aminosulfonyl.
 3. The compound according to claim 1, which is (1) 5-(5-{[2-(2-methoxyphenyl)ethyl]amino}pentanoyl)-2,3-dihydro-1-benzofuran-7-sulfonamide or a salt thereof, (2) 5-(5-{[2-(2-chlorophenyl)ethyl]amino}pentanoyl)-2,3-dihydro-1-benzofuran-7-sulfonamide or a salt thereof, (3) 5-{5-[[2-(2-methoxyphenyl)ethyl](methyl)amino]pentanoyl}-2,3-dihydro-1-benzofuran-7-sulfonamide or a salt thereof, (4) 5-{5-[[2-(2-chlorophenyl)ethyl](methyl)amino]pentanoyl}-2,3-dihydro-1-benzofuran-7-sulfonamide or a salt thereof, (5) N-isopropyl-5-(5-{[2-(2-methoxyphenyl)ethyl]amino}pentanoyl)-2,3-dihydro-1-benzofuran-7-sulfonamide or a salt thereof, (6) 5-(5-{[2-(2-chlorophenyl)ethyl]amino}pentanoyl)-N-isopropyl-2,3-dihydro-1-benzofuran-7-sulfonamide or a salt thereof, (7) N-isopropyl-5-{5-[[2-(2-methoxyphenyl)ethyl](methyl)amino]pentanoyl}-2,3-dihydro-1-benzofuran-7-sulfonamide or a salt thereof, (8) 5-{5-[[2-(2-chlorophenyl)ethyl](methyl)amino]pentanoyl}-N-isopropyl-2,3-dihydro-1-benzofuran-7-sulfonamide or a salt thereof, (9) N-methyl-5-(5-{[2-(2-methoxyphenyl)ethyl]amino}pentanoyl)-2,3-dihydro-1-benzofuran-7-sulfonamide or a salt thereof, (10) N-methyl-5-(5-{[2-(2-chlorophenyl)ethyl]amino}pentanoyl)-2,3-dihydro-1-benzofuran-7-sufonamide or a salt thereof, (11) N,N-dimethyl-5-(5-{[2-(2-methoxyphenyl)ethyl]amino}pentanoyl)-2,3-dihydro-1-benzofuran-7-sulfonamide or a salt thereof, (12) N,N-dimethyl-5-(5-{[2-(2-chlorophenyl)ethyl]amino}pentanoyl)-2,3-dihydro-1-benzofuran-7-sulfonamide or a salt thereof, (13) 5-{5-[[2-(2-methoxyphenyl)ethyl](methyl)amino]pentanoyl}-N-methyl-2,3-dihydro-1-benzofuran-7-sulfonamide or a salt thereof, (14) 5-{5-[[2-(2-chlorophenyl)ethyl](methyl)amino]pentanoyl}-N-methyl-2,3-dihydro-1-benzofuran-7-sulfonamide or a salt thereof, (15)5-{5-[[2-(2-methoxyphenyl)ethyl](methyl)amino]pentanoyl}-N,N-dimethyl-2,3-dihydro-1-benzofuran-7-sulfonamide or a salt thereof, or (16) 5-{5-[[2-(2-chlorophenyl)ethyl](methyl)amino]pentanoyl}-N,N-dimethyl-2,3-dihydro-1-benzofuran-7-sulfonamide or a salt thereof. 